Next Article in Journal
A Review: Highlighting the Links between Epigenetics, COVID-19 Infection, and Vitamin D
Next Article in Special Issue
Association between LAG3/CD4 Genes Variants and Risk for Multiple Sclerosis
Previous Article in Journal
Magneto-Fluorescent Mesoporous Nanocarriers for the Dual-Delivery of Ofloxacin and Doxorubicin to Tackle Opportunistic Bacterial Infections in Colorectal Cancer
Previous Article in Special Issue
Norovirus Intestinal Infection and Lewy Body Disease in an Older Patient with Acute Cognitive Impairment
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain

Lucas E. Cabrera Zapata
Luis Miguel Garcia-Segura
María Julia Cambiasso
1,3,* and
Maria Angeles Arevalo
Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Córdoba, Córdoba 5016, Argentina
Instituto Cajal (IC), Consejo Superior de Investigaciones Científicas (CSIC), 28002 Madrid, Spain
Cátedra de Biología Celular, Facultad de Odontología, Universidad Nacional de Córdoba, Córdoba 5000, Argentina
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(20), 12288;
Submission received: 23 September 2022 / Revised: 10 October 2022 / Accepted: 11 October 2022 / Published: 14 October 2022
(This article belongs to the Special Issue State-of-the-Art Molecular Neurobiology in Spain)


For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

1. Sex and Brain: Not All about Gonadal Hormones

Sex differences in the brain, found at a wide range of levels from neuronal and glial functions to anatomical, physiological and behavioral phenotypes, are now understood to be the result of two major factors acting across the lifespan: (1) a sex-specific trophic environment due to differences in the secretion of gonadal hormones and (2) a distinct genetic and epigenetic pattern depending on sex, generated by differences in the expression of genes linked to the X and Y sex chromosomes. However, it took several decades of research to first identify these factors as generators of phenotypic sex differences in the brain and then to begin to comprehend how they act to shape sex-specific neural circuits, often interacting with each other and with the environment in complex ways. Although sex differences in the human brain can also be found and discussed in terms of sexual orientation and gender identity [1], with “female” and “male” being frequently used to define gender, this review focuses on addressing sex differences in the brain in terms of biological sex without discussing gender identity. Thus, to avoid misinterpretations, we have circumscribed here the definitions of “female” as an XX individual carrying ovaries and “male” as an XY individual carrying testes.
Towards the end of the 1950s, Charles H. Phoenix, Robert W. Goy, Arnold A. Gerall and William C. Young performed a series of experiments that would lay the groundwork for beginning to understand how gonadal hormones affect the developing brain to establish a sex-specific neural substrate. These authors reported for the first time how prenatal testosterone administration in rodents irreversibly affected mating sexual behavior in adulthood, masculinizing and defeminizing its expression in females [2]. In the following years, numerous articles were published pointing out the relevance of the perinatal action of gonadal steroids in the definition of adult reproductive behavior [3,4,5,6]. This important corpus of evidence was the basis for the formulation of the classical hypothesis of brain sexual differentiation, which holds that sex differences in the central nervous system are a direct consequence of gonadal steroids, postulating two types of actions for these hormones in the brain: organizational and activational. Organizational actions describe the effects that gonadal hormones have on shaping neural circuitry during gestational and early postnatal development, whereas activational actions refer to the physiological/behavioral responses of the sexually differentiated adult brain to sex steroids [7]. According to this hypothesis, during a perinatal sensitive/critical period (in rodents starting around embryonic day 18 —E18— and ending around postnatal day 10 —P10—), testosterone produced by the developing testes and its metabolites, dihydrotestosterone (DHT) and 17β-estradiol (E2) [8,9,10], actively organize male-type brain circuits, such that, in adulthood, these circuits respond to the activational effects of gonadal hormones by displaying typically male behaviors. In females, on the contrary, the absence of gonadal secretions during this period leads to the development of a female brain, which will be able to generate female-specific physiological/behavioral responses to the appropriate hormonal influence in adulthood [11,12,13,14].
With the organizational/activational hypothesis of brain sexual differentiation, the idea that differences associated with the X and Y chromosomes may contribute to the sex-dependent development of non-gonadal tissues lagged long behind. For years, the role of X and Y as factors causing sex differences in the brain were not properly addressed, mainly due to the enormous amount of experimental evidence that emerged during the second half of the 20th century pointing to sex hormones as the sole determinant of phenotypic sex differences in vertebrates and, importantly, because of the lack of experimental tools that would allow clear discernment of sex chromosome effects independently of gonadal secretions. However, over the last decades, with the development of genetic engineering and the generation of certain transgenic animals, it has been possible to identify numerous sex differences in the brain whose origin and development are either completely independent of sex hormones or cannot be explained solely through their action [15,16]. These partial or total gonad-independent sex differences are tightly controlled by genetics and epigenetics of sex chromosomes.

2. Sex Chromosome Complement and Brain Sex Differences

The concept of sex determination refers to the process by which it is defined, in early embryogenesis, to follow a female or male sexual differentiation pathway, which is directly controlled by the sex chromosome complement of the original zygote. In mammals, the alternative sex chromosome complements are XX (two copies of the X chromosome, one inherited from the father and the other from the mother) and XY (the X chromosome inherited from the mother and the Y chromosome inherited from the father), with XX individuals being determined as females and XY as males [17]. This is mainly due to the existence of the testis-determining Sry gene on the Y chromosome, which begins to be expressed in early embryogenesis (around E10.5 in mice) in the undifferentiated gonads of XY individuals to drive the process of testis differentiation. In XX individuals, certain autosomal and X-linked genes, which are silenced by Sry in XY embryos, induce the ovarian differentiation program [18,19].
Some of the earliest evidence for the development of sexually differentiated phenotypes independent of hormonal action was obtained from the study of cells/tissues isolated from embryos before the onset of gonadal secretion of sex hormones and their influence on brain organization, i.e., before the critical period of perinatal sensitivity [20,21,22]. For instance, Pilgrim’s laboratory showed in rats a greater number of dopaminergic neurons in mesencephalic cultures from females than from males, as well as a higher content of the neurotransmitter dopamine in neurons derived from diencephalon of females. Interestingly, treatment of cultures with E2 or testosterone did not eliminate sex differences. Since all neuronal cultures were established from E14 embryos (a developmental time well before the onset of the critical period in rats), these differences found between female and male dopaminergic neurons cannot be explained by the sexually dimorphic action of gonadal secretions [23,24].
Another set of evidence of great interest for its implications in the understanding of complex sex-specific behaviors in adult animals came from the study of birds. In zebra finches (Taeniopygia guttata), males produce a courtship song that females are unable to perform, the neural circuitry responsible for controlling this song being much larger and more elaborate in males [25]. Although it has been observed that estrogen treatment of newborn females leads to the development of a song due to masculinization of the brain regions that control it [26,27], and that blockade of these steroids in males prevents complete masculinization [28], these effects are always partial, often not observed at all, or require estrogen/androgen doses for masculinization of females much higher than physiological levels measured in males, making a purely hormonal explanation unlikely [29]. In contrast to mammals, male birds are homogametic (with a ZZ sex chromosome complement) and female birds are heterogametic (with a ZW complement). The discovery of a finch with bilateral gynandromorphism made it possible to evaluate, to some extent, the impact of the sex chromosome complement on the generation of male and female phenotypes. These “half-male, half-female” finches have a testis and male plumage on the right half of the body and an ovary and female plumage on the left half. By in situ hybridization, it was shown that W-linked genes were expressed almost exclusively on the left half of the brain, whereas Z-specific genes were expressed ubiquitously but at markedly higher levels on the right half of the brain, as when comparing ZW males with ZZ females. Furthermore, despite the fact that the whole brain developed in the same environment of circulating gonadal hormones, the brain regions governing singing were much larger on the right hemisphere than on the left hemisphere, an effect that can only be attributed to the difference in the sex chromosome complement of cells from one half of the brain and the other [30].
The development of certain transgenic mice has allowed a major leap in the study of sex chromosome complement as a determinant of phenotypic sex differences in the last two decades. One of these transgenic models is the Four Core Genotypes (FCG) mouse, which combines two mutations in the same murine line: a spontaneous deletion of the Sry gene from the Y chromosome, generating a “Y minus” or “Y” [31], and the subsequent reinsertion of this gene into autosome 3 [32,33]. Thus, it was possible to dissociate the inheritance of the Y chromosome from that of the Sry gene and the subsequent differentiation of testes, generating mice whose gonadal phenotype (testes/ovaries) is independent of the sex chromosome complement (XY/XX). Mice that inherit an X chromosome, a Y chromosome and the Sry reinserted on chromosome 3 (XYSry mice), develop testes and in adulthood are fertile males. Breeding XYSry males with XX females makes it possible to obtain the four different genotypes that give the model its name: XX females (XXf), XY females (XYf), XYSry males (XYm) and XXSry males (XXm). Comparison of a variable among these four groups allows independent assessment of the effects of the factors: (1) gonadal sex (testes/ovaries and the hormonal environment associated with each type of gonad), (2) genetic sex (XY/XX sex chromosome complement) and (3) the interaction between these two factors (Figure 1). The main advantage of the FCG model is that the sex chromosome effects can be measured even after gonadal differentiation, so that the assessment of the genetic sex role is not restricted to the stage prior to the perinatal critical period.
FCG mice have been widely used in recent years in the study of sexual differentiation of the brain, allowing for a clearer assessment of the specific contributions of gonadal hormones and sex chromosome complement. In the first published work using the murine model for this purpose, a sex difference in the proportion of dopaminergic neurons due to sex chromosomes was demonstrated in mesencephalic neuronal cultures from E14.5 FCG embryos: at both 6 and 11 days in vitro, cultures derived from XY embryos had significantly more dopaminergic neurons (immunoreactive for tyrosine hydroxylase) than those derived from XX, regardless of the gonadal sex of the donors [34]. In another series of studies using adult FCG animals, a higher density of vasopressin-immunoreactive fibers was reported in the lateral septum of XY compared to XX mice without effect of gonadal sex, observing, in turn, more aggressive and less parental care behaviors in gonadal male and XYf mice than in XXf mice, with evidence associating these behavioral sex differences with those found at the level of the vasopressinergic system [35,36]. In this case, although the reported sex differences depend directly on the sex chromosome complement, it is evident how the organizational/activational influence of testicular secretions masculinizes and defeminizes the behavior of XXm mice, indicating synergistic effects between the sex chromosome complement and the hormonal environment to sex-specifically differentiate the assessed behaviors. The effect of sex chromosomes in determining sexually dimorphic expression patterns for autosomal genes, including genes encoding transcription factors, enzymes and neurotransmitters, has been explored by some laboratories. A remarkable case is Cyp19a1, a gene located on chromosome 9 in mouse and coding for aromatase, the enzyme catalyzing testosterone conversion to E2 not only in the gonads but, importantly, in the brain [37,38]. Higher aromatase mRNA and protein expression in stria terminalis and anterior amygdala has been reported in XY than in XX E16 FCG mice. E2 or DHT stimulation of amygdala neuronal cultures derived from E15 embryos resulted in increased aromatase expression only in XX neurons, thus abolishing sex differences observed under control conditions [39,40,41]. Similarly, hippocampal neuronal cultures from E17 wild-type mice also showed greater aromatase mRNA levels in XY than in XX neurons [42]. Several other works using FCG mice have provided valuable evidence on sex chromosome complement involvement in determining sex differences in Alzheimer’s disease vulnerability [43], response to nociceptive stimuli [44], habit formation [45], autoimmune disease susceptibility [46], developmental neural tube defects [47], bradycardic baroreflex response [48], sodium appetite and renin-angiotensin system [49,50] and ethanol intake [51], among others [52].

3. Genetics and Epigenetics of the X and Y Chromosomes and Sexual Differentiation

In mammals, sex chromosomes have evolved under different selective pressures that generated an extreme and more than evident divergence between the two, not observed in any other homologous pair. It has been proposed that the mammalian X and Y chromosomes evolved from an ordinary autosomal pair that began to diverge at least 180 million years ago [53,54,55]. The first differentiating event would have been the acquisition of a testis-determining gene or region on the “proto-Y” autosome, from which the Sry gene would evolve. Subsequently, a series of large-scale inversion mutations occurred mainly on this chromosome, leading to a drastic restriction in its ability to recombine with the X during meiosis. Finally, most of the Y underwent genetic degeneration due to deletions and loss of entire genes, which together reduced it to minimal expression. In parallel and responding to this gradual reduction of the Y, a complex mechanism of wide transcriptional silencing of one of the two Xs in females, known as the X chromosome inactivation (XCI), began to develop as a process that compensates for the dosage imbalance of X-linked genes between XX and XY individuals [55,56,57].
As a result of this divergent evolution, the modern Y is considerably smaller than the X and contains only 48 known protein-coding genes in humans and 12 in mouse, most of which serve functions restricted to testicular determination and spermatogenesis [58]. Some of these genes reside in the small pseudoautosomal regions (PARs) located at the ends of both X and Y chromosomes. PARs share sequence identity since they recombine as autosomal regions during meiosis [59]. While humans have two PARs per sex chromosome, PAR1 on Xp/Yp and PAR2 on Xq/Yq, each containing only about 15 and 4 genes, respectively, mice carry a single PAR with two genes only [60,61,62,63]. Therefore, most genes on the X and Y chromosomes are located in the regions between the PARs, which are the male specific region of the Y (MSY) and the non-PAR of the X (Figure 2). Although MSY genes cannot recombine with X and are male-specific, some of them still retain an X-linked counterpart with which they share some level of remaining homology and are ubiquitously expressed in the organism [56,64]. These X/Y homologs are highly dosage-sensitive and conserved among mammals. This suggests that deleterious effects due to the loss of the Y-linked copy during Y degeneration and the subsequent decreased expression probably acted as selective pressures favoring the conservation of one copy on each sex chromosome for these loci [65,66,67]. Some important X/Y homologs include Kdm6a-Utx/Kdm6c-Uty, Kdm5c/Kdm5d, Ddx3x/Ddx3y, Usp9x/Usp9y, and Eif2s3x/Eif2s3y.
The X, on the other hand, is much larger than the Y and contains more than 1000 genes, of which more than 800 code for proteins in humans and mice [58]. As mentioned above, the existence of two Xs in XX individuals and only one in XY individuals causes a dosage imbalance in the copy number of virtually all of the X-linked genes between the sexes, with the exception of those encoded on PARs. This imbalance is compensated during early embryogenesis by XCI, which silences transcription of one of the two Xs in each cell of the XX blastocysts. Thus, XCI defines a transcriptionally inactive X (Xi) and a transcriptionally active X (Xa) that will be clonally inherited by mitosis to all the cells eventually shaping an XX organism [64,68]. The molecular mechanism by which XCI occurs is extremely complex and includes the selective expression from and physical coating of the future Xi of multiple copies of the Xist (X-inactive specific transcript) long noncoding RNA, as well as the accumulation of repressive methylation marks on histones and DNA, all of which contribute to the heterochromatic conformation of the silenced X [69,70,71,72]. Since XX individuals inherit one X from the father and the other from the mother and XCI in eutherian mammals randomly inactivates one of the two Xs in each of the embryonic cells, the ultimate result is a mosaic phenotype or mosaicism for the expression of heterozygous loci, with some patches of cells expressing the paternal and others the maternal X genes [64,68,73].
However, despite the XCI mechanism, imbalances in the expression levels of X-linked genes can still occur between males and females. Firstly, it is now known that all chromosomes received by a new individual are inherited carrying a number of epigenetic marks that will condition their expression and that are different depending on whether the paternal or maternal chromosome is considered for each homologous pair, a phenomenon called genomic imprinting [74]. Thus, some X-linked genes could be expressed to a greater or lesser extent depending on whether the allele is inherited from the father or the mother, so that, in XX individuals, silencing one or the other X in each cell would not have exactly the same effect. Moreover, in XY individuals the X is always inherited from the mother, which means that for these individuals the imprinting of the X is always maternal [75,76,77,78]. Secondly, XCI does not result in complete repression of all Xi genes, as some “escape” inactivation and can thus be expressed from both the Xa and the Xi [79]. In humans, about 23% of X-linked genes are consistently expressed from both copies in XX cells, so their expression levels are significantly higher in these cells compared to XY cells [80,81]. In mice, about 7% of X-linked genes escape inactivation [82]. Notably, while some X genes consistently escape XCI in all species, individuals and tissues studied, many others vary significantly in the extent of their escape depending on species, individuals of the same species, developmental stage, cell or tissue type and health/disease condition [83,84,85,86].
Therefore, considering the particular nature of sex chromosomes and their inheritance, it is possible to identify at least five mechanisms potentially involved in the establishment of sex differences independently of the action of gonadal hormones (Figure 2): (1) expression of MSY-linked genes (only present in XY individuals), (2) increased expression in XX individuals of X-linked genes escaping XCI, (3) reduced expression of PARs-linked genes in XX individuals due to XCI, (4) differences in X gene expression due to genomic imprinting and (5) sequestration of transcriptional regulators such as heterochromatin assembly factors and other epigenetic modifiers for Xi silencing in XX individuals, which would limit the availability of such factors for regulation of autosomal gene expression [15,58,81,87,88]. Delving into these differentiation mechanisms is contributing to the final understanding of sex chromosome dosage effects on genome-wide autosomal expression, which are already known to span a diversity of cellular functions such as cell fate, cell-cycle regulation, chromatin organization, immune response signaling, protein trafficking and energy metabolism [58,65,89,90,91].

4. X-Linked Genes and Sexual Differentiation of the Brain

Although the X chromosome does not comprise more than 5% of the human and mouse genomes, it exhibits an interesting characteristic for neurobiology: a unique enrichment in the number of brain-relevant genes, containing nearly a sixfold greater number of genes involved in neurodevelopmental and neurophysiological processes than autosomes [92,93,94]. Furthermore, studies assessing mRNA levels clearly show that X-linked genes are expressed at higher levels in the nervous system than in other tissues, both in mice and humans [94,95,96]. Mutations in several of these genes cause different disorders characterized by cognitive impairment and commonly referred to as X-linked mental retardation (XLMR) conditions, with Rett syndrome, Fragile X syndrome and Börjeson-Forssman–Lehmann syndrome being just a few [97,98,99].
Among the numerous X-linked genes involved in neurodevelopment and neurophysiology, we can highlight, for example, Kdm6a, Kdm5c, Mecp2, Hdac8, Morf4l2, Msl3, Phf6, Ddx3x, Eif2s3x, Fmr1, Usp9x, Mid1, Ogt, Syp and Tmem47. Several of these genes encode epigenetic regulators of transcription. This is the case of the histone demethylases KDM6A and KDM5C [100], the methylated DNA-binding protein MECP2 [101], the histone deacetylase HDAC8 [102], the component MSL3 of the MSL acetyltransferase complex [103] and the component MORF4L2 of the NuA4 histone acetyltransferase and mSin3a histone deacetylase complexes [104]. Others encode transcription factors such as PHF6 [105], proteins involved in translation and mRNA metabolism such as DDX3X, EIF2S3X and FMR1 [106,107,108], modulators of protein activity through posttranslational modifications such us deubiquitinase USP9X, ubiquitin ligase MID1 and glycosyltransferase OGT [109,110,111], or integral membrane proteins such us TMEM47/BCMP1 and the synaptic vesicle-protein synaptophysin (SYP) [112,113]. All these X-linked genes are most likely involved in the development of sex differences in the brain, making their study at that level extremely interesting [88,114]. Notably, most of the X genes actively involved in the sexual differentiation of the brain belong to the very small group of the X/Y homologs (e.g., Kdm6a, Kdm5c, Ddx3x), with X homologs having evolved the pattern of escape from XCI and commonly expressing higher in XX than in XY individuals. Here we will review important evidence emerging especially in the last 5 years that points to some of these genes as critical factors in brain sexual differentiation.
Kdm6a (or Utx) encodes a histone demethylase enzyme that promotes chromatin accessibility by removing repressive H3K27 methylation [115,116]. It is a non-PAR X-linked gene and retains a Y homolog, Kdm6c or Uty, although in vivo demethylase activity of this Y counterpart is almost lost and its physiological role as an H3K27 demethylase is currently under discussion [117,118]. KDM6A not only promotes gene expression by catalyzing H3K27 demethylation, but also through demethylation-independent functions by interacting with H3K4 methylation complexes and H3K27 acetyltransferases [119,120,121,122]. Thus, KDM6A is a key epigenetic modifier promoting chromatin accessibility and transcription genome wide. In XX individuals, Kdm6a consistently escapes XCI in different mouse and human tissues, including the brain, resulting in higher KDM6A expression in XX than in XY individuals [81,82,123,124,125].
In the nervous system, Kdm6a is involved in the determination of neural stem cells and their subsequent differentiation into glial cells and neurons [122,126,127,128,129]. HOX genes are a major target of KDM6A during cell differentiation, with the demethylase being required for the removal of H3K27me3 at promoter regions and subsequent expression of HOXB1, HOXD10, HOXD11 and HOXD12 [130,131]. During retinoic acid-induced neuronal differentiation of human embryonic stem cells in vitro, preferential recruitment of KDM6A for H3K27 demethylation and transcriptional activation of HOX genes of clusters A, B, C and D has been reported [132]. Kdm6a deletion during brain development leads to severe defects in multiple areas including cerebral cortex, hippocampus and hypothalamus, often with different effects for males and females. For instance, whereas homozygous knockout of Kdm6a is fatal in female mice around 11–12 days of embryonic development due to severe heart malformations and neural tube closure defects, knockout male mice survive to adulthood and are fertile, suggesting that the presence of Y-linked Uty in males is partially preventing the deleterious effects of Kdm6a loss [117,133]. Kdm6a deficiency by knockdown and conditional knockout in the developing cerebral cortex increased neural stem cells proliferation in basal layers (ventricular and subventricular zones) and decreased the number of differentiated neurons in the upper layer (cortical plate) at E16.5/E17.5, these effects being less significant in males than in females [134]. Regarding the hippocampus, Kdm6a conditional deletion during embryonic development in mice resulted in repression of autosomal genes involved in neuritogenesis and synaptogenesis, impaired dendritic maturation, functional alterations in synaptic plasticity, deficits in spatial learning and increased anxiety-like behaviors [135]. Remarkably, such studies were conducted using only Kdm6a knockout males, as virtually all knockout females died within 3 weeks after birth [135].
The presence of two functional copies of Kdm6a in XX versus just one copy in XY embryos is required for the expression of early sex-specific phenotypes in the developing hypothalamus before gonadal hormones organize the brain. In FCG mice, hypothalamic neurons carrying two X chromosomes showed higher Kdm6a mRNA levels than XY neurons, regardless of gonadal sex. Remarkably, this XX > XY expression pattern was not affected by different hormonal conditions between embryonic (E14) and postnatal (P0, P60) ages or by the treatment with E2 of hypothalamic neurons in vitro, indicating that sex differences in Kdm6a expression are directly dependent on X chromosome dosage and are not modulated by sex hormones [136]. Before brain exposure to gonadal secretions (i.e., prior to the critical period), cultured XX hypothalamic neurons exhibit a more accelerated differentiation than cultured XY neurons, in terms of neuritic arborization complexity and axonal length, with these sex differences being dependent on the bHLH neuritogenic factor neurogenin 3 (Ngn3), which expression is increased in XX neurons [137,138]. Kdm6a is an upstream regulator of these sex differences in the neuritogenic development of hypothalamic neurons, expressing higher in XX than in XY neurons and being XX-specifically required for H3K27me3 demethylation at the Ngn3 promoter region, upregulation of Ngn3 expression and, subsequently, the promotion of axonal growth [136,139]. Importantly, among relevant proneural factors controlling hypothalamic neuronal differentiation, Kdm6a not only promotes the expression of Ngn3, but also of bHLH transcription factors Ascl1 (Mash1), Neurod1 and Neurod2 and the neuron-specific activator of cyclin-dependent kinase 5 (CDK5) Cdk5r1 (p35), albeit in a sex-independent manner in all these cases except for Ngn3 [136,139]. Recently, it has been demonstrated that Kdm6a is also required for the expression of neuropeptides POMC and NPY, molecular markers of hypothalamic neuronal populations involved in the regulation of energy homeostasis and food intake. In sex-segregated hypothalamic neuronal cultures of E14 mice, Pomc and Npy showed sex-dependent and opposite expression patterns at both mRNA and protein levels, with female neurons expressing more Pomc and less Npy than male neurons. ChIP-qPCR data for H3K27me3 at Pomc and Npy promoter regions showed higher methylation levels in male than in female neurons, consistent with the higher expression of Kdm6a in females. Kdm6a knockdown induced an enrichment of H3K27me3 at Pomc and Npy promoters only in female neurons without affecting male neurons, showing that Kdm6a promotes chromatin accessibility at these loci specifically in females [139]. Together, evidence indicates that Kdm6a mediates these sex differences in Pomc and Npy expression by acting in females, not only through H3K27me3 demethylation at these loci, but also through activation of the bHLH Ascl1/Ngn3 axis [139], both transcription factors that play a key role in regulating POMC+ and NPY+ cell fate specification in hypothalamus [140,141]. The effects of Uty, the Y homolog of Kdm6a, on these differentiation processes between XX and XY hypothalamic neurons have not been addressed in this model, so the question of whether Uty, which was conserved during Y evolution, might somehow be compensating for sex differences caused by Kdm6a dosage remains unanswered.
Loss-of-function mutations in KDM6A lead to Kabuki syndrome, a congenital disorder characterized by cognitive deficits, facial, skeletal and cardiac abnormalities and growth retardation [142,143,144]. As in many other X-linked diseases, male patients, who carry a single X and thus a single copy of KDM6A, tend to be more severely affected [145]. In a study assessing sex differences in vulnerability to Alzheimer’s disease, it was proposed that a second X chromosome in women confers resilience to the disease specifically through KDM6A [43]. Although many more women live with Alzheimer’s disease [146], largely due to their longer life expectancy, affected men die earlier and usually show more severe forms of the disease, with higher neurodegeneration and cognitive decline [147,148], despite similar β-amyloid (Aβ) and tau deposition between sexes [149,150,151]. XY neurons showed greater cell death than XX neurons when exposed in vitro to the neurotoxin Aβ, with modest Kdm6a overexpression reducing neurotoxicity in XY neurons and Kdm6a knockdown increasing it in XX neurons. Similarly, in mice engineered to express mutated forms of the human amyloid precursor protein (hAPP mice), individuals carrying a single X showed reduced longevity and worse spatial learning and memory performance compared to XX mice; when Kdm6a was overexpressed using lentivirus in the hippocampus of XY-hAPP mice, a significant improvement in learning and memory performance was observed in these animals compared to control XY-hAPP mice. Thus, the presence of a single X/Kdm6a copy consistently worsened hAPP/Aβ-related mortality, cognitive impairment and cellular viability compared to two X/Kdm6a copies. Finally, KDM6A expression in the human brain was higher in women than in men and in Alzheimer’s disease patients compared to controls. Considering all these observations in the human brain and in mouse models of the disease, authors suggested that having two copies of Kdm6a compared to just one copy of the gene confers stronger resilience to the disease, and speculated that increased KDM6A in brains of people with Alzheimer’s disease might be a neuroprotective, compensatory response [43].
KDM5C is another X-linked histone demethylase escaping XCI [81] and involved in sexual differentiation of the brain. Contrary to KDM6A, KDM5C activity contributes to repressed gene expression through H3K4 demethylation, with H3K4me3 being an epigenetic modification enriched in open, transcriptionally active chromatin sites [152,153]. Increased expression of Kdm5c in XX versus XY microglia has been associated with sex differences in microglial reactivity and microglia-mediated neuroinflammation after stroke in mice. After inducing ischemic stroke by middle cerebral artery occlusion, aged mice carrying two vs. one X chromosome, regardless of gonadal sex, showed larger infarct volumes, worse behavioral deficits, more robust microglial activation with increased pro-inflammatory TNFα and IL-1β and reduced anti-inflammatory IL-10 cytokines, and enhanced co-localization of KDM5C with the microglia marker IBA1 [154]. Remarkably, the expression of interferon regulatory factor 4 (IRF4), an important microglial anti-inflammatory element, was shown to be repressed by KDM5C H3K4 demethylation activity [155]. These results indicate an X dosage-dependent effect on stroke sensitivity, with microglial reactivity and microglia-mediated neuroinflammation after injury more exacerbated in XX vs. XY. Postmenopausal women show a greater vulnerability to stroke than men of the same age [156], so further research in this field could contribute to understanding whether sex chromosomes are involved and which X- and/or Y-linked genes regulate these sex differences. Interestingly, higher expression of Kdm6a in females has also been linked to neuroinflammation in mice, which might help shed light on women’s increased susceptibility to autoimmune diseases of the central nervous system such as multiple sclerosis. Using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, which recapitulates CD4+ T cell-dependent disease, Itoh, et al. [157] showed that KDM6A deletion in CD4+ T cells ameliorated clinical disease, reduced neuropathology and downregulated the expression of neuroinflammation pathway genes, also providing an X dosage-dependent mechanism for sex differences in autoimmune diseases affecting the nervous system. Like KDM6A, KDM5C is also an important chromatin remodeler controlling transcriptional programs within neurons to impact their differentiation, neuritic growth and synaptic activity [158,159,160,161,162], with KDM5C mutations leading to Claes-Jensen X-linked intellectual disability [163,164,165], although further studies including sex as a critical variable are needed.
Ddx3x codes for an evolutionarily conserved DEAD-box RNA helicase that participates in numerous cellular events, such as mRNA synthesis, splicing, mRNA transport, translation and Wnt/β-catenin signaling pathway regulation [166,167,168]. Mutated forms of Ddx3x have been detected in different cancer types and are associated with intellectual disability (DDX3X syndrome), brain malformations, autism and epilepsy [108,169,170]. Most DDX3X syndrome individuals are female, an observation leading to the idea that the Y-linked homolog DDX3Y can compensate for DDX3X loss and contribute to milder phenotypes in males carrying DDX3X mutations [171,172]. Complete loss of Ddx3x in a conditional knockout (Ddx3x-cKO) mouse model led to microcephaly only in females, which might suggest that expression of the Y-linked homolog Ddx3y explains why Ddx3x-cKO male mice are phenotypically milder than Ddx3x-cKO females [173]. In addition, loss of one versus two Ddx3x copies caused vastly different corticogenesis phenotypes: Ddx3x-cKO females presented profound apoptosis in neural progenitors and neurons in the developing neocortex, whereas heterozygous females and Ddx3x-cKO males had impaired neurogenesis without cell death. Ddx3x-depleted progenitors exhibited prolonged cell division and more proliferative divisions at the expense of symmetric neurogenic divisions, affecting neural fates and reducing the generation of neurons. Finally, Ddx3y depletion phenocopies of cortical neurogenesis defects were observed in Ddx3x-cKO males, suggesting that Ddx3y can compensate for Ddx3x loss in males, an observation consistent with previous findings in both the hindbrain and hematopoietic system [174,175]. Similar results were reported by Lennox, et al. [176], with transient depletion of Ddx3x in the developing mouse neocortex disrupting corticogenesis by altering newborn cells distribution between cortical layers (more cells in the ventricular and subventricular zones and less in the cortical plate compared to control) and neuronal differentiation. Mechanistically, this impaired cortical neurogenesis after Ddx3x loss was suggested to be cause by defective helicase activity, formation of aberrant RNA-protein cytoplasmic granules and impaired translation of DDX3X-dependent mRNA targets observed in pathogenic DDX3X missense mutations [176].

5. Y-Linked Genes and Sexual Differentiation of the Brain

As mentioned above, X and Y chromosomes evolved from an autosomal pair and through a long process in which the original genetic information carried by the Y chromosome was severely reduced. Only about 3% of the ancestral genes originally located on the human Y chromosome still survive [177,178], in contrast to 98% of the ancestral genes on the X chromosome [179]. However, this loss/survival of Y genes did not occur randomly, but was subject to selection and strongly influenced by evolution of X and XCI. Evidence shows that most of the genes conserved on the modern Y have been retained due to selection because they belong to one of two categories: (1) genes playing male-specific functions in gametogenesis or reproductive development and (2) genes that are dosage-sensitive, broadly expressed X/Y homologs (mentioned above) [56,65,66]. Notably, surviving genes of the first category, such as SRY, HSFY, TSPY and RBMY, have shown a functional divergence from their X homologues (SOX3, HSFX, TSPX and RBMX, respectively) to control male reproduction. Nonetheless, because all Y genes have been exposed to selective pressure only in males, even widely expressed ancestral Y homologs may exhibit subtle differences in sequence and function from their X-linked pairs [55,56,66].
Contrary to the growing interest and research on X-linked genes in recent years, very little research has been carried out to delve into the role of specific Y-linked genes in the sexual differentiation of the brain. This is partly a consequence of the generalized belief that the Y chromosome encodes just a handful of protein-coding genes only important for male reproduction along with a much larger proportion of repetitive and/or noncoding “junk” genetic material. Although some studies have recently demonstrated, as discussed in the previous section, that expression of Y homologs of X/Y gene pairs such as Uty, Ddx3y and Nlgn4y is critical during brain development in males [117,133,173,174,180], ensuring a two-dose autosomal-like expression for these loci in XY that matches expression levels in XX (the latter carrying two active gene copies due to XCI escape), further research addressing the specific functions of Y-encoded homologs and differences with their X-linked counterparts at developmental and physiological levels is required. Of note, there has been recent interest in the Y noncoding genome and its contribution to both sex determination and other traits in health and disease [181]. For instance, at least six Y-linked long noncoding RNAs were found to be expressed in a time- and tissue-specific pattern in the developing brain of newborn chimpanzees, all sharing characteristics that suggest a potential functional role in brain development conserved in human and chimpanzee males [182]. Again, while quite intriguing and with great future potential, studies in this area are just beginning to yield results. Table 1 summarizes the X- and Y-linked genes discussed in this review and their main cellular functions.

6. Concluding Remarks

Today we know that the contribution of the X and Y chromosomes to the sexual differentiation of the brain and other non-gonadal tissues begins in the zygote itself and continues throughout life, via the differential expression of genes linked to these chromosomes per se and their influence on the expression of autosomal genes [58,88,89]. Importantly, both differentiating factors, i.e., sex chromosomes and gonadal hormones, can converge and interact on a given trait in a synergistic or antagonistic manner, establishing differences between the sexes or offsetting their effects and resulting in the attenuation/compensation of differences [183,184,185].
It took several decades of research and effort to comprehensibly identify sex chromosomes as causative factors of sex-specific phenotypes beyond sex/gonadal determination, and it was not until recent years that specific genes encoded by sex chromosomes began to be identified as agents of brain sexual differentiation. Due to the development of transgenic mouse models and powerful genetic tools to rigorously control the expression of particular genes in a time- and region-specific manner, both in vitro and in vivo, we are a little closer every day to a precise understanding of the action of X- and Y-linked genes in the brain. Hopefully, in the coming years we will be able to use this precise knowledge to address diseases with sex-biased phenomenology in the developing and aging brain.

Author Contributions

All authors participated in the conception of the article. L.E.C.Z. elaborated figures and wrote the first draft of the manuscript. All authors edited and revised the manuscript. All authors have read and agreed to the published version of the manuscript.


This work was supported by grants from: (1) Argentina: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PUE 2016 No. 22920160100135CO), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, PICT 2015 No. 1333 and PICT 2019 No. 2176) and Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC, 2018–2021) to M.J.C.; (2) Spain: Agencia Estatal de Investigación (AEI, BFU2017-82754-R and PID2020-115019RB-I00), Fondo Europeo de Desarrollo Regional (FEDER), and Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES)-Instituto de Salud Carlos III to M.A.A. and the Enhancing Mobility between Latin America, Caribbean and the European Union in Health and Environment (EMHE)-CSIC Program (MHE-200057) to L.M.G.-S. and M.J.C.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.


We thank EMHE-CSIC Program, Secretaría General Iberoamericana (SEGIB), Fundación Carolina (Spain) and the International Brain Research Organization-Latin America Regional Committee (IBRO-LARC) for financially supporting part of Lucas E. Cabrera Zapata’s work abroad at the Instituto Cajal, Madrid, Spain.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Bao, A.M.; Swaab, D.F. Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders. Front. Neuroendocrinol. 2011, 32, 214–226. [Google Scholar] [CrossRef] [PubMed]
  2. Phoenix, C.H.; Goy, R.W.; Gerall, A.A.; Young, W.C. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 1959, 65, 369–382. [Google Scholar] [CrossRef] [PubMed]
  3. Beach, F.A.; Noble, R.G.; Orndoff, R.K. Effects of perinatal androgen treatment on responses of male rats to gonadal hormones in adulthood. J. Comp. Physiol. Psychol. 1969, 68, 490–497. [Google Scholar] [CrossRef]
  4. Stern, J.J. Neonatal castration, androstenedione, and the mating behavior of the male rat. J. Comp. Physiol. Psychol. 1969, 69, 608–612. [Google Scholar] [CrossRef] [PubMed]
  5. Baum, M.J. A comparison of the effects of methyltrienolone (R 1881) and 5 alpha-dihydrotestosterone on sexual behavior of castrated male rats. Horm. Behav. 1979, 13, 165–174. [Google Scholar] [CrossRef]
  6. Baum, M.J.; Gallagher, C.A.; Martin, J.T.; Damassa, D.A. Effects of testosterone, dihydrotestosterone, or estradiol administered neonatally on sexual behavior of female ferrets. Endocrinology 1982, 111, 773–780. [Google Scholar] [CrossRef] [PubMed]
  7. Arnold, A.P.; Gorski, R.A. Gonadal steroid induction of structural sex differences in the central nervous system. Annu. Rev. Neurosci. 1984, 7, 413–442. [Google Scholar] [CrossRef] [PubMed]
  8. Warren, D.W.; Haltmeyer, G.C.; Eik-Nes, K.B. Testosterone in the fetal rat testis. Biol. Reprod. 1973, 8, 560–565. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Huhtaniemi, I. Fetal testis—a very special endocrine organ. Eur. J. Endocrinol. 1994, 130, 25–31. [Google Scholar] [CrossRef] [Green Version]
  10. O’Shaughnessy, P.J.; Baker, P.J.; Johnston, H. The foetal Leydig cell—Differentiation, function and regulation. Int. J. Androl. 2006, 29, 90–95; discussion 105–108. [Google Scholar] [CrossRef]
  11. MacLusky, N.J.; Naftolin, F. Sexual differentiation of the central nervous system. Science 1981, 211, 1294–1302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Wilson, C.A.; Davies, D.C. The control of sexual differentiation of the reproductive system and brain. Reproduction 2007, 133, 331–359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. McCarthy, M.M. Estradiol and the developing brain. Physiol. Rev. 2008, 88, 91–124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Negri-Cesi, P.; Colciago, A.; Pravettoni, A.; Casati, L.; Conti, L.; Celotti, F. Sexual differentiation of the rodent hypothalamus: Hormonal and environmental influences. J. Steroid Biochem. Mol. Biol. 2008, 109, 294–299. [Google Scholar] [CrossRef] [PubMed]
  15. Arnold, A.P. Sex Differences in the Age of Genetics. In Hormones, Brain, and Behavior, 3rd ed.; Pfaff, D.W., Joëls, M., Eds.; Academic Press, Elsevier: Toronto, ON, Canada, 2017; Volume 5, pp. 33–48. [Google Scholar]
  16. Arnold, A.P.; Burgoyne, P.S. Are XX and XY brain cells intrinsically different? Trends Endocrinol. Metab. 2004, 15, 6–11. [Google Scholar] [CrossRef] [PubMed]
  17. Charlesworth, B. The evolution of chromosomal sex determination and dosage compensation. Curr. Biol. 1996, 6, 149–162. [Google Scholar] [CrossRef] [Green Version]
  18. Goodfellow, P.N.; Lovell-Badge, R. SRY and sex determination in mammals. Annu. Rev. Genet. 1993, 27, 71–92. [Google Scholar] [CrossRef] [PubMed]
  19. Makela, J.A.; Koskenniemi, J.J.; Virtanen, H.E.; Toppari, J. Testis Development. Endocr. Rev. 2019, 40, 857–905. [Google Scholar] [CrossRef] [PubMed]
  20. Cambiasso, M.J.; Diaz, H.; Caceres, A.; Carrer, H.F. Neuritogenic effect of estradiol on rat ventromedial hypothalamic neurons co-cultured with homotopic or heterotopic glia. J. Neurosci. Res. 1995, 42, 700–709. [Google Scholar] [CrossRef] [PubMed]
  21. Carrer, H.F.; Cambiasso, M.J. Sexual differentiation of the brain: Genes, estrogen, and neurotrophic factors. Cell. Mol. Neurobiol. 2002, 22, 479–500. [Google Scholar] [CrossRef] [PubMed]
  22. Reisert, I.; Pilgrim, C. Sexual differentiation of monoaminergic neurons—Genetic or epigenetic? Trends Neurosci. 1991, 14, 468–473. [Google Scholar] [CrossRef]
  23. Engele, J.; Pilgrim, C.; Reisert, I. Sexual differentiation of mesencephalic neurons in vitro: Effects of sex and gonadal hormones. Int. J. Dev. Neurosci. 1989, 7, 603–611. [Google Scholar] [CrossRef]
  24. Beyer, C.; Pilgrim, C.; Reisert, I. Dopamine content and metabolism in mesencephalic and diencephalic cell cultures: Sex differences and effects of sex steroids. J. Neurosci. 1991, 11, 1325–1333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Nottebohm, F.; Arnold, A.P. Sexual dimorphism in vocal control areas of the songbird brain. Science 1976, 194, 211–213. [Google Scholar] [CrossRef]
  26. Gurney, M.E.; Konishi, M. Hormone-induced sexual differentiation of brain and behavior in zebra finches. Science 1980, 208, 1380–1383. [Google Scholar] [CrossRef]
  27. Simpson, H.B.; Vicario, D.S. Early estrogen treatment of female zebra finches masculinizes the brain pathway for learned vocalizations. J. Neurobiol. 1991, 22, 777–793. [Google Scholar] [CrossRef]
  28. Holloway, C.C.; Clayton, D.F. Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro. Nat. Neurosci. 2001, 4, 170–175. [Google Scholar] [CrossRef]
  29. Arnold, A.P. Sexual differentiation of the zebra finch song system: Positive evidence, negative evidence, null hypotheses, and a paradigm shift. J. Neurobiol. 1997, 33, 572–584. [Google Scholar] [CrossRef]
  30. Agate, R.J.; Grisham, W.; Wade, J.; Mann, S.; Wingfield, J.; Schanen, C.; Palotie, A.; Arnold, A.P. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. Proc. Natl. Acad. Sci. USA 2003, 100, 4873–4878. [Google Scholar] [CrossRef] [Green Version]
  31. Lovell-Badge, R.; Robertson, E. XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development 1990, 109, 635–646. [Google Scholar] [CrossRef]
  32. Mahadevaiah, S.K.; Odorisio, T.; Elliott, D.J.; Rattigan, A.; Szot, M.; Laval, S.H.; Washburn, L.L.; McCarrey, J.R.; Cattanach, B.M.; Lovell-Badge, R.; et al. Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities. Hum. Mol. Genet. 1998, 7, 715–727. [Google Scholar] [CrossRef] [PubMed]
  33. Itoh, Y.; Mackie, R.; Kampf, K.; Domadia, S.; Brown, J.D.; O’Neill, R.; Arnold, A.P. Four core genotypes mouse model: Localization of the Sry transgene and bioassay for testicular hormone levels. BMC Res. Notes 2015, 8, 69. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Carruth, L.L.; Reisert, I.; Arnold, A.P. Sex chromosome genes directly affect brain sexual differentiation. Nat. Neurosci. 2002, 5, 933–934. [Google Scholar] [CrossRef] [PubMed]
  35. De Vries, G.J.; Rissman, E.F.; Simerly, R.B.; Yang, L.Y.; Scordalakes, E.M.; Auger, C.J.; Swain, A.; Lovell-Badge, R.; Burgoyne, P.S.; Arnold, A.P. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J. Neurosci. 2002, 22, 9005–9014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Gatewood, J.D.; Wills, A.; Shetty, S.; Xu, J.; Arnold, A.P.; Burgoyne, P.S.; Rissman, E.F. Sex chromosome complement and gonadal sex influence aggressive and parental behaviors in mice. J. Neurosci. 2006, 26, 2335–2342. [Google Scholar] [CrossRef] [Green Version]
  37. Simpson, E.R.; Mahendroo, M.S.; Means, G.D.; Kilgore, M.W.; Hinshelwood, M.M.; Graham-Lorence, S.; Amarneh, B.; Ito, Y.; Fisher, C.R.; Michael, M.D.; et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 1994, 15, 342–355. [Google Scholar] [CrossRef]
  38. Brooks, D.C.; Coon, V.J.; Ercan, C.M.; Xu, X.; Dong, H.; Levine, J.E.; Bulun, S.E.; Zhao, H. Brain Aromatase and the Regulation of Sexual Activity in Male Mice. Endocrinology 2020, 161, bqaa137. [Google Scholar] [CrossRef]
  39. Cisternas, C.D.; Garcia-Segura, L.M.; Cambiasso, M.J. Hormonal and genetic factors interact to control aromatase expression in the developing brain. J. Neuroendocrinol. 2018, 30, e12535. [Google Scholar] [CrossRef]
  40. Cisternas, C.D.; Cabrera Zapata, L.E.; Arevalo, M.A.; Garcia-Segura, L.M.; Cambiasso, M.J. Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERbeta and sex chromosome complement. Sci. Rep. 2017, 7, 5320. [Google Scholar] [CrossRef] [Green Version]
  41. Cisternas, C.D.; Tome, K.; Caeiro, X.E.; Dadam, F.M.; Garcia-Segura, L.M.; Cambiasso, M.J. Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain. Mol. Cell. Endocrinol. 2015, 414, 99–110. [Google Scholar] [CrossRef]
  42. Ruiz-Palmero, I.; Ortiz-Rodriguez, A.; Melcangi, R.C.; Caruso, D.; Garcia-Segura, L.M.; Rune, G.M.; Arevalo, M.A. Oestradiol synthesized by female neurons generates sex differences in neuritogenesis. Sci. Rep. 2016, 6, 31891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Davis, E.J.; Broestl, L.; Abdulai-Saiku, S.; Worden, K.; Bonham, L.W.; Minones-Moyano, E.; Moreno, A.J.; Wang, D.; Chang, K.; Williams, G.; et al. A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease. Sci. Transl. Med. 2020, 12, eaaz5677. [Google Scholar] [CrossRef]
  44. Gioiosa, L.; Chen, X.; Watkins, R.; Klanfer, N.; Bryant, C.D.; Evans, C.J.; Arnold, A.P. Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice. Horm. Behav. 2008, 53, 124–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Quinn, J.J.; Hitchcott, P.K.; Umeda, E.A.; Arnold, A.P.; Taylor, J.R. Sex chromosome complement regulates habit formation. Nat. Neurosci. 2007, 10, 1398–1400. [Google Scholar] [CrossRef]
  46. Smith-Bouvier, D.L.; Divekar, A.A.; Sasidhar, M.; Du, S.; Tiwari-Woodruff, S.K.; King, J.K.; Arnold, A.P.; Singh, R.R.; Voskuhl, R.R. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 2008, 205, 1099–1108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Chen, X.; Watkins, R.; Delot, E.; Reliene, R.; Schiestl, R.H.; Burgoyne, P.S.; Arnold, A.P. Sex difference in neural tube defects in p53-null mice is caused by differences in the complement of X not Y genes. Dev. Neurobiol. 2008, 68, 265–273. [Google Scholar] [CrossRef]
  48. Caeiro, X.E.; Mir, F.R.; Vivas, L.M.; Carrer, H.F.; Cambiasso, M.J. Sex chromosome complement contributes to sex differences in bradycardic baroreflex response. Hypertension 2011, 58, 505–511. [Google Scholar] [CrossRef] [Green Version]
  49. Dadam, F.M.; Caeiro, X.E.; Cisternas, C.D.; Macchione, A.F.; Cambiasso, M.J.; Vivas, L. Effect of sex chromosome complement on sodium appetite and Fos-immunoreactivity induced by sodium depletion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 306, R175–R184. [Google Scholar] [CrossRef]
  50. Dadam, F.M.; Cisternas, C.D.; Macchione, A.F.; Godino, A.; Antunes-Rodrigues, J.; Cambiasso, M.J.; Vivas, L.M.; Caeiro, X.E. Sex chromosome complement involvement in angiotensin receptor sexual dimorphism. Mol. Cell. Endocrinol. 2017, 447, 98–105. [Google Scholar] [CrossRef]
  51. Sneddon, E.A.; Rasizer, L.N.; Cavalco, N.G.; Jaymes, A.H.; Ostlie, N.J.; Minshall, B.L.; Masters, B.M.; Hughes, M.R.; Hrncir, H.; Arnold, A.P.; et al. Gonadal hormones and sex chromosome complement differentially contribute to ethanol intake, preference, and relapse-like behaviour in four core genotypes mice. Addict. Biol. 2022, 27, e13222. [Google Scholar] [CrossRef]
  52. Arnold, A.P. Four Core Genotypes and XY* mouse models: Update on impact on SABV research. Neurosci. Biobehav. Rev. 2020, 119, 1–8. [Google Scholar] [CrossRef]
  53. Muller, H.J. Genetic Variability, Twin Hybrids and Constant Hybrids, in a Case of Balanced Lethal Factors. Genetics 1918, 3, 422–499. [Google Scholar] [CrossRef] [PubMed]
  54. Muller, H.J. A gene for the fourth chromosome of Drosophila. J. Exp. Zool. 1914, 17, 325–336. [Google Scholar] [CrossRef] [Green Version]
  55. Graves, J.A. Sex chromosome specialization and degeneration in mammals. Cell 2006, 124, 901–914. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Hughes, J.F.; Page, D.C. The Biology and Evolution of Mammalian Y Chromosomes. Annu. Rev. Genet. 2015, 49, 507–527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Graves, J.A. Evolution of vertebrate sex chromosomes and dosage compensation. Nat. Rev. Genet. 2016, 17, 33–46. [Google Scholar] [CrossRef] [PubMed]
  58. Wijchers, P.J.; Festenstein, R.J. Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 2011, 27, 132–140. [Google Scholar] [CrossRef]
  59. Simmler, M.C.; Rouyer, F.; Vergnaud, G.; Nystrom-Lahti, M.; Ngo, K.Y.; de la Chapelle, A.; Weissenbach, J. Pseudoautosomal DNA sequences in the pairing region of the human sex chromosomes. Nature 1985, 317, 692–697. [Google Scholar] [CrossRef]
  60. Charchar, F.J.; Svartman, M.; El-Mogharbel, N.; Ventura, M.; Kirby, P.; Matarazzo, M.R.; Ciccodicola, A.; Rocchi, M.; D’Esposito, M.; Graves, J.A. Complex events in the evolution of the human pseudoautosomal region 2 (PAR2). Genome Res. 2003, 13, 281–286. [Google Scholar] [CrossRef] [Green Version]
  61. Monteiro, B.; Arenas, M.; Prata, M.J.; Amorim, A. Evolutionary dynamics of the human pseudoautosomal regions. PLoS Genet. 2021, 17, e1009532. [Google Scholar] [CrossRef]
  62. Perry, J.; Palmer, S.; Gabriel, A.; Ashworth, A. A short pseudoautosomal region in laboratory mice. Genome Res. 2001, 11, 1826–1832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Morgan, A.P.; Bell, T.A.; Crowley, J.J.; Pardo-Manuel de Villena, F. Instability of the Pseudoautosomal Boundary in House Mice. Genetics 2019, 212, 469–487. [Google Scholar] [CrossRef] [PubMed]
  64. Morey, C.; Avner, P. Genetics and epigenetics of the X chromosome. Ann. N. Y. Acad. Sci. 2010, 1214, E18–E33. [Google Scholar] [CrossRef] [PubMed]
  65. Raznahan, A.; Parikshak, N.N.; Chandran, V.; Blumenthal, J.D.; Clasen, L.S.; Alexander-Bloch, A.F.; Zinn, A.R.; Wangsa, D.; Wise, J.; Murphy, D.G.M.; et al. Sex-chromosome dosage effects on gene expression in humans. Proc. Natl. Acad. Sci. USA 2018, 115, 7398–7403. [Google Scholar] [CrossRef] [Green Version]
  66. Bellott, D.W.; Hughes, J.F.; Skaletsky, H.; Brown, L.G.; Pyntikova, T.; Cho, T.J.; Koutseva, N.; Zaghlul, S.; Graves, T.; Rock, S.; et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature 2014, 508, 494–499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Cortez, D.; Marin, R.; Toledo-Flores, D.; Froidevaux, L.; Liechti, A.; Waters, P.D.; Grutzner, F.; Kaessmann, H. Origins and functional evolution of Y chromosomes across mammals. Nature 2014, 508, 488–493. [Google Scholar] [CrossRef] [PubMed]
  68. Lyon, M.F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 1961, 190, 372–373. [Google Scholar] [CrossRef] [PubMed]
  69. Lee, J.T.; Bartolomei, M.S. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 2013, 152, 1308–1323. [Google Scholar] [CrossRef] [Green Version]
  70. Gayen, S.; Maclary, E.; Hinten, M.; Kalantry, S. Sex-specific silencing of X-linked genes by Xist RNA. Proc. Natl. Acad. Sci. USA 2016, 113, E309–E318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Penny, G.D.; Kay, G.F.; Sheardown, S.A.; Rastan, S.; Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 1996, 379, 131–137. [Google Scholar] [CrossRef]
  72. Marahrens, Y.; Loring, J.; Jaenisch, R. Role of the Xist gene in X chromosome choosing. Cell 1998, 92, 657–664. [Google Scholar] [CrossRef] [Green Version]
  73. Disteche, C.M.; Berletch, J.B. X-chromosome inactivation and escape. J. Genet. 2015, 94, 591–599. [Google Scholar] [CrossRef] [Green Version]
  74. Babak, T.; DeVeale, B.; Tsang, E.K.; Zhou, Y.; Li, X.; Smith, K.S.; Kukurba, K.R.; Zhang, R.; Li, J.B.; van der Kooy, D.; et al. Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat. Genet. 2015, 47, 544–549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Davies, W.; Isles, A.; Smith, R.; Karunadasa, D.; Burrmann, D.; Humby, T.; Ojarikre, O.; Biggin, C.; Skuse, D.; Burgoyne, P.; et al. Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat. Genet. 2005, 37, 625–629. [Google Scholar] [CrossRef] [PubMed]
  76. Raefski, A.S.; O’Neill, M.J. Identification of a cluster of X-linked imprinted genes in mice. Nat. Genet. 2005, 37, 620–624. [Google Scholar] [CrossRef] [PubMed]
  77. Thornhill, A.R.; Burgoyne, P.S. A paternally imprinted X chromosome retards the development of the early mouse embryo. Development 1993, 118, 171–174. [Google Scholar] [CrossRef] [PubMed]
  78. Kobayashi, S.; Isotani, A.; Mise, N.; Yamamoto, M.; Fujihara, Y.; Kaseda, K.; Nakanishi, T.; Ikawa, M.; Hamada, H.; Abe, K.; et al. Comparison of gene expression in male and female mouse blastocysts revealed imprinting of the X-linked gene, Rhox5/Pem, at preimplantation stages. Curr. Biol. 2006, 16, 166–172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Berletch, J.B.; Yang, F.; Disteche, C.M. Escape from X inactivation in mice and humans. Genome Biol. 2010, 11, 213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Carrel, L.; Willard, H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005, 434, 400–404. [Google Scholar] [CrossRef] [PubMed]
  81. Tukiainen, T.; Villani, A.C.; Yen, A.; Rivas, M.A.; Marshall, J.L.; Satija, R.; Aguirre, M.; Gauthier, L.; Fleharty, M.; Kirby, A.; et al. Landscape of X chromosome inactivation across human tissues. Nature 2017, 550, 244–248. [Google Scholar] [CrossRef]
  82. Berletch, J.B.; Ma, W.; Yang, F.; Shendure, J.; Noble, W.S.; Disteche, C.M.; Deng, X. Escape from X inactivation varies in mouse tissues. PLoS Genet. 2015, 11, e1005079. [Google Scholar] [CrossRef]
  83. Peeters, S.B.; Cotton, A.M.; Brown, C.J. Variable escape from X-chromosome inactivation: Identifying factors that tip the scales towards expression. Bioessays 2014, 36, 746–756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Balaton, B.P.; Brown, C.J. Escape Artists of the X Chromosome. Trends Genet. 2016, 32, 348–359. [Google Scholar] [CrossRef] [PubMed]
  85. Navarro-Cobos, M.J.; Balaton, B.P.; Brown, C.J. Genes that escape from X-chromosome inactivation: Potential contributors to Klinefelter syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 2020, 184, 226–238. [Google Scholar] [CrossRef] [PubMed]
  86. Garieri, M.; Stamoulis, G.; Blanc, X.; Falconnet, E.; Ribaux, P.; Borel, C.; Santoni, F.; Antonarakis, S.E. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. Proc. Natl. Acad. Sci. USA 2018, 115, 13015–13020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Burgoyne, P.S.; Arnold, A.P. A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol. Sex Differ. 2016, 7, 68. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Arnold, A.P. X chromosome agents of sexual differentiation. Nat. Rev. Endocrinol. 2022, 18, 574–583. [Google Scholar] [CrossRef] [PubMed]
  89. Wijchers, P.J.; Yandim, C.; Panousopoulou, E.; Ahmad, M.; Harker, N.; Saveliev, A.; Burgoyne, P.S.; Festenstein, R. Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. Dev. Cell 2010, 19, 477–484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Bermejo-Alvarez, P.; Rizos, D.; Rath, D.; Lonergan, P.; Gutierrez-Adan, A. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc. Natl. Acad. Sci. USA 2010, 107, 3394–3399. [Google Scholar] [CrossRef] [Green Version]
  91. Blencowe, M.; Chen, X.; Zhao, Y.; Itoh, Y.; McQuillen, C.N.; Han, Y.; Shou, B.L.; McClusky, R.; Reue, K.; Arnold, A.P.; et al. Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation. Genome Res. 2022, 32, 807–824. [Google Scholar] [CrossRef] [PubMed]
  92. Zechner, U.; Wilda, M.; Kehrer-Sawatzki, H.; Vogel, W.; Fundele, R.; Hameister, H. A high density of X-linked genes for general cognitive ability: A run-away process shaping human evolution? Trends Genet. 2001, 17, 697–701. [Google Scholar] [CrossRef]
  93. Ross, M.T.; Grafham, D.V.; Coffey, A.J.; Scherer, S.; McLay, K.; Muzny, D.; Platzer, M.; Howell, G.R.; Burrows, C.; Bird, C.P.; et al. The DNA sequence of the human X chromosome. Nature 2005, 434, 325–337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Nguyen, D.K.; Disteche, C.M. High expression of the mammalian X chromosome in brain. Brain Res. 2006, 1126, 46–49. [Google Scholar] [CrossRef]
  95. Deng, X.; Hiatt, J.B.; Nguyen, D.K.; Ercan, S.; Sturgill, D.; Hillier, L.W.; Schlesinger, F.; Davis, C.A.; Reinke, V.J.; Gingeras, T.R.; et al. Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat. Genet. 2011, 43, 1179–1185. [Google Scholar] [CrossRef] [Green Version]
  96. Nguyen, D.K.; Disteche, C.M. Dosage compensation of the active X chromosome in mammals. Nat. Genet. 2006, 38, 47–53. [Google Scholar] [CrossRef]
  97. Ropers, H.H.; Hamel, B.C. X-linked mental retardation. Nat. Rev. Genet. 2005, 6, 46–57. [Google Scholar] [CrossRef] [PubMed]
  98. Chiurazzi, P.; Schwartz, C.E.; Gecz, J.; Neri, G. XLMR genes: Update 2007. Eur. J. Hum. Genet. 2008, 16, 422–434. [Google Scholar] [CrossRef] [PubMed]
  99. Vacca, M.; Della Ragione, F.; Scalabri, F.; D’Esposito, M. X inactivation and reactivation in X-linked diseases. Semin. Cell Dev. Biol. 2016, 56, 78–87. [Google Scholar] [CrossRef] [PubMed]
  100. Shen, H.; Xu, W.; Lan, F. Histone lysine demethylases in mammalian embryonic development. Exp. Mol. Med. 2017, 49, e325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Hoffbuhr, K.C.; Moses, L.M.; Jerdonek, M.A.; Naidu, S.; Hoffman, E.P. Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype. Ment. Retard. Dev. Disabil. Res. Rev. 2002, 8, 99–105. [Google Scholar] [CrossRef] [PubMed]
  102. Deardorff, M.A.; Porter, N.J.; Christianson, D.W. Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders. Protein Sci. 2016, 25, 1965–1976. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Kadlec, J.; Hallacli, E.; Lipp, M.; Holz, H.; Sanchez-Weatherby, J.; Cusack, S.; Akhtar, A. Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nat. Struct. Mol. Biol. 2011, 18, 142–149. [Google Scholar] [CrossRef] [PubMed]
  104. Chen, M.; Tominaga, K.; Pereira-Smith, O.M. Emerging role of the MORF/MRG gene family in various biological processes, including aging. Ann. N. Y. Acad. Sci. 2010, 1197, 134–141. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Jahani-Asl, A.; Cheng, C.; Zhang, C.; Bonni, A. Pathogenesis of Borjeson-Forssman-Lehmann syndrome: Insights from PHF6 function. Neurobiol. Dis. 2016, 96, 227–235. [Google Scholar] [CrossRef] [Green Version]
  106. Xu, J.; Watkins, R.; Arnold, A.P. Sexually dimorphic expression of the X-linked gene Eif2s3x mRNA but not protein in mouse brain. Gene Expr. Patterns 2006, 6, 146–155. [Google Scholar] [CrossRef]
  107. Bagni, C.; Oostra, B.A. Fragile X syndrome: From protein function to therapy. Am. J. Med. Genet. A 2013, 161, 2809–2821. [Google Scholar] [CrossRef]
  108. Snijders Blok, L.; Madsen, E.; Juusola, J.; Gilissen, C.; Baralle, D.; Reijnders, M.R.; Venselaar, H.; Helsmoortel, C.; Cho, M.T.; Hoischen, A.; et al. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. Am. J. Hum. Genet. 2015, 97, 343–352. [Google Scholar] [CrossRef] [Green Version]
  109. Stegeman, S.; Jolly, L.A.; Premarathne, S.; Gecz, J.; Richards, L.J.; Mackay-Sim, A.; Wood, S.A. Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFbeta-mediated axonogenesis. PLoS ONE 2013, 8, e68287. [Google Scholar] [CrossRef] [Green Version]
  110. Lu, T.; Chen, R.; Cox, T.C.; Moldrich, R.X.; Kurniawan, N.; Tan, G.; Perry, J.K.; Ashworth, A.; Bartlett, P.F.; Xu, L.; et al. X-linked microtubule-associated protein, Mid1, regulates axon development. Proc. Natl. Acad. Sci. USA 2013, 110, 19131–19136. [Google Scholar] [CrossRef] [Green Version]
  111. Levine, Z.G.; Walker, S. The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells? Annu. Rev. Biochem. 2016, 85, 631–657. [Google Scholar] [CrossRef]
  112. Gordon, S.L.; Cousin, M.A. X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval. J. Neurosci. 2013, 33, 13695–13700. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Christophe-Hobertus, C.; Szpirer, C.; Guyon, R.; Christophe, D. Identification of the gene encoding Brain Cell Membrane Protein 1 (BCMP1), a putative four-transmembrane protein distantly related to the Peripheral Myelin Protein 22/Epithelial Membrane Proteins and the Claudins. BMC Genom. 2001, 2, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Raznahan, A.; Disteche, C.M. X-chromosome regulation and sex differences in brain anatomy. Neurosci. Biobehav. Rev. 2021, 120, 28–47. [Google Scholar] [CrossRef] [PubMed]
  115. Hong, S.; Cho, Y.W.; Yu, L.R.; Yu, H.; Veenstra, T.D.; Ge, K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc. Natl. Acad. Sci. USA 2007, 104, 18439–18444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Tran, N.; Broun, A.; Ge, K. Lysine Demethylase KDM6A in Differentiation, Development, and Cancer. Mol. Cell. Biol. 2020, 40, e00341-20. [Google Scholar] [CrossRef]
  117. Shpargel, K.B.; Sengoku, T.; Yokoyama, S.; Magnuson, T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet. 2012, 8, e1002964. [Google Scholar] [CrossRef] [Green Version]
  118. Walport, L.J.; Hopkinson, R.J.; Vollmar, M.; Madden, S.K.; Gileadi, C.; Oppermann, U.; Schofield, C.J.; Johansson, C. Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J. Biol. Chem. 2014, 289, 18302–18313. [Google Scholar] [CrossRef] [Green Version]
  119. Cho, Y.W.; Hong, T.; Hong, S.; Guo, H.; Yu, H.; Kim, D.; Guszczynski, T.; Dressler, G.R.; Copeland, T.D.; Kalkum, M.; et al. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J. Biol. Chem. 2007, 282, 20395–20406. [Google Scholar] [CrossRef] [Green Version]
  120. Tie, F.; Banerjee, R.; Conrad, P.A.; Scacheri, P.C.; Harte, P.J. Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Mol. Cell. Biol. 2012, 32, 2323–2334. [Google Scholar] [CrossRef] [Green Version]
  121. Wang, S.P.; Tang, Z.; Chen, C.W.; Shimada, M.; Koche, R.P.; Wang, L.H.; Nakadai, T.; Chramiec, A.; Krivtsov, A.V.; Armstrong, S.A.; et al. A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription. Mol. Cell 2017, 67, 308–321.e6. [Google Scholar] [CrossRef]
  122. Wang, C.; Lee, J.E.; Cho, Y.W.; Xiao, Y.; Jin, Q.; Liu, C.; Ge, K. UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc. Natl. Acad. Sci. USA 2012, 109, 15324–15329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Greenfield, A.; Carrel, L.; Pennisi, D.; Philippe, C.; Quaderi, N.; Siggers, P.; Steiner, K.; Tam, P.P.; Monaco, A.P.; Willard, H.F.; et al. The UTX gene escapes X inactivation in mice and humans. Hum. Mol. Genet. 1998, 7, 737–742. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Xu, J.; Deng, X.; Watkins, R.; Disteche, C.M. Sex-specific differences in expression of histone demethylases Utx and Uty in mouse brain and neurons. J. Neurosci. 2008, 28, 4521–4527. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Armoskus, C.; Moreira, D.; Bollinger, K.; Jimenez, O.; Taniguchi, S.; Tsai, H.W. Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus. Brain Res. 2014, 1562, 23–38. [Google Scholar] [CrossRef] [Green Version]
  126. Yang, X.; Xu, B.; Mulvey, B.; Evans, M.; Jordan, S.; Wang, Y.D.; Pagala, V.; Peng, J.; Fan, Y.; Patel, A.; et al. Differentiation of human pluripotent stem cells into neurons or cortical organoids requires transcriptional co-regulation by UTX and 53BP1. Nat. Neurosci. 2019, 22, 362–373. [Google Scholar] [CrossRef] [PubMed]
  127. Shan, Y.; Zhang, Y.; Zhao, Y.; Wang, T.; Zhang, J.; Yao, J.; Ma, N.; Liang, Z.; Huang, W.; Huang, K.; et al. JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells. Nat. Commun. 2020, 11, 382. [Google Scholar] [CrossRef] [Green Version]
  128. Subhramanyam, C.S.; Cao, Q.; Wang, C.; Heng, Z.S.L.; Zhou, Z.; Hu, Q. Role of PIWI-like 4 in modulating neuronal differentiation from human embryonal carcinoma cells. RNA Biol. 2020, 17, 1613–1624. [Google Scholar] [CrossRef]
  129. Tang, Q.Y.; Zhang, S.F.; Dai, S.K.; Liu, C.; Wang, Y.Y.; Du, H.Z.; Teng, Z.Q.; Liu, C.M. UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters. Stem Cell Rep. 2020, 15, 439–453. [Google Scholar] [CrossRef]
  130. Agger, K.; Cloos, P.A.; Christensen, J.; Pasini, D.; Rose, S.; Rappsilber, J.; Issaeva, I.; Canaani, E.; Salcini, A.E.; Helin, K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 2007, 449, 731–734. [Google Scholar] [CrossRef]
  131. Lan, F.; Bayliss, P.E.; Rinn, J.L.; Whetstine, J.R.; Wang, J.K.; Chen, S.; Iwase, S.; Alpatov, R.; Issaeva, I.; Canaani, E.; et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 2007, 449, 689–694. [Google Scholar] [CrossRef]
  132. Shahhoseini, M.; Taghizadeh, Z.; Hatami, M.; Baharvand, H. Retinoic acid dependent histone 3 demethylation of the clustered HOX genes during neural differentiation of human embryonic stem cells. Biochem. Cell Biol. 2013, 91, 116–122. [Google Scholar] [CrossRef] [PubMed]
  133. Welstead, G.G.; Creyghton, M.P.; Bilodeau, S.; Cheng, A.W.; Markoulaki, S.; Young, R.A.; Jaenisch, R. X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner. Proc. Natl. Acad. Sci. USA 2012, 109, 13004–13009. [Google Scholar] [CrossRef] [Green Version]
  134. Lei, X.; Jiao, J. UTX Affects Neural Stem Cell Proliferation and Differentiation through PTEN Signaling. Stem Cell Rep. 2018, 10, 1193–1207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Tang, G.B.; Zeng, Y.Q.; Liu, P.P.; Mi, T.W.; Zhang, S.F.; Dai, S.K.; Tang, Q.Y.; Yang, L.; Xu, Y.J.; Yan, H.L.; et al. The Histone H3K27 Demethylase UTX Regulates Synaptic Plasticity and Cognitive Behaviors in Mice. Front. Mol. Neurosci. 2017, 10, 267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Cabrera Zapata, L.E.; Cisternas, C.D.; Sosa, C.; Garcia-Segura, L.M.; Arevalo, M.A.; Cambiasso, M.J. X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons. Cell. Mol. Life Sci. 2021, 78, 7043–7060. [Google Scholar] [CrossRef]
  137. Cisternas, C.D.; Cabrera Zapata, L.E.; Mir, F.R.; Scerbo, M.J.; Arevalo, M.A.; Garcia-Segura, L.M.; Cambiasso, M.J. Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons. Sci. Rep. 2020, 10, 8223. [Google Scholar] [CrossRef] [PubMed]
  138. Scerbo, M.J.; Freire-Regatillo, A.; Cisternas, C.D.; Brunotto, M.; Arevalo, M.A.; Garcia-Segura, L.M.; Cambiasso, M.J. Neurogenin 3 mediates sex chromosome effects on the generation of sex differences in hypothalamic neuronal development. Front. Cell. Neurosci. 2014, 8, 188. [Google Scholar] [CrossRef] [Green Version]
  139. Cabrera Zapata, L.E.; Cambiasso, M.J.; Arevalo, M.A. Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner. Front. Cell Dev. Biol. 2022, 10, 937875. [Google Scholar] [CrossRef]
  140. Pelling, M.; Anthwal, N.; McNay, D.; Gradwohl, G.; Leiter, A.B.; Guillemot, F.; Ang, S.L. Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus. Dev. Biol. 2011, 349, 406–416. [Google Scholar] [CrossRef] [Green Version]
  141. Anthwal, N.; Pelling, M.; Claxton, S.; Mellitzer, G.; Collin, C.; Kessaris, N.; Richardson, W.D.; Gradwohl, G.; Ang, S.L. Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity. Dis. Models Mech. 2013, 6, 1133–1145. [Google Scholar] [CrossRef]
  142. Miyake, N.; Mizuno, S.; Okamoto, N.; Ohashi, H.; Shiina, M.; Ogata, K.; Tsurusaki, Y.; Nakashima, M.; Saitsu, H.; Niikawa, N.; et al. KDM6A point mutations cause Kabuki syndrome. Hum. Mutat. 2013, 34, 108–110. [Google Scholar] [CrossRef] [PubMed]
  143. Van Laarhoven, P.M.; Neitzel, L.R.; Quintana, A.M.; Geiger, E.A.; Zackai, E.H.; Clouthier, D.E.; Artinger, K.B.; Ming, J.E.; Shaikh, T.H. Kabuki syndrome genes KMT2D and KDM6A: Functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum. Mol. Genet. 2015, 24, 4443–4453. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Bogershausen, N.; Gatinois, V.; Riehmer, V.; Kayserili, H.; Becker, J.; Thoenes, M.; Simsek-Kiper, P.O.; Barat-Houari, M.; Elcioglu, N.H.; Wieczorek, D.; et al. Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Hum. Mutat. 2016, 37, 847–864. [Google Scholar] [CrossRef] [Green Version]
  145. Faundes, V.; Goh, S.; Akilapa, R.; Bezuidenhout, H.; Bjornsson, H.T.; Bradley, L.; Brady, A.F.; Brischoux-Boucher, E.; Brunner, H.; Bulk, S.; et al. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2. Genet. Med. 2021, 23, 1202–1210. [Google Scholar] [CrossRef]
  146. Dubal, D.B. Sex difference in Alzheimer’s disease: An updated, balanced and emerging perspective on differing vulnerabilities. Handb. Clin. Neurol. 2020, 175, 261–273. [Google Scholar] [CrossRef] [PubMed]
  147. Buckley, R.F.; Mormino, E.C.; Amariglio, R.E.; Properzi, M.J.; Rabin, J.S.; Lim, Y.Y.; Papp, K.V.; Jacobs, H.I.L.; Burnham, S.; Hanseeuw, B.J.; et al. Sex, amyloid, and APOE epsilon4 and risk of cognitive decline in preclinical Alzheimer’s disease: Findings from three well-characterized cohorts. Alzheimers Dement. 2018, 14, 1193–1203. [Google Scholar] [CrossRef] [PubMed]
  148. Casaletto, K.B.; Elahi, F.M.; Staffaroni, A.M.; Walters, S.; Contreras, W.R.; Wolf, A.; Dubal, D.; Miller, B.; Yaffe, K.; Kramer, J.H. Cognitive aging is not created equally: Differentiating unique cognitive phenotypes in “normal” adults. Neurobiol. Aging 2019, 77, 13–19. [Google Scholar] [CrossRef] [PubMed]
  149. Jack, C.R., Jr.; Wiste, H.J.; Weigand, S.D.; Knopman, D.S.; Vemuri, P.; Mielke, M.M.; Lowe, V.; Senjem, M.L.; Gunter, J.L.; Machulda, M.M.; et al. Age, Sex, and APOE epsilon4 Effects on Memory, Brain Structure, and beta-Amyloid Across the Adult Life Span. JAMA Neurol. 2015, 72, 511–519. [Google Scholar] [CrossRef] [Green Version]
  150. Jack, C.R., Jr.; Therneau, T.M.; Wiste, H.J.; Weigand, S.D.; Knopman, D.S.; Lowe, V.J.; Mielke, M.M.; Vemuri, P.; Roberts, R.O.; Machulda, M.M.; et al. Transition rates between amyloid and neurodegeneration biomarker states and to dementia: A population-based, longitudinal cohort study. Lancet Neurol. 2016, 15, 56–64. [Google Scholar] [CrossRef] [Green Version]
  151. Jack, C.R., Jr.; Wiste, H.J.; Weigand, S.D.; Therneau, T.M.; Knopman, D.S.; Lowe, V.; Vemuri, P.; Mielke, M.M.; Roberts, R.O.; Machulda, M.M.; et al. Age-specific and sex-specific prevalence of cerebral beta-amyloidosis, tauopathy, and neurodegeneration in cognitively unimpaired individuals aged 50–95 years: A cross-sectional study. Lancet Neurol. 2017, 16, 435–444. [Google Scholar] [CrossRef]
  152. Iwase, S.; Lan, F.; Bayliss, P.; de la Torre-Ubieta, L.; Huarte, M.; Qi, H.H.; Whetstine, J.R.; Bonni, A.; Roberts, T.M.; Shi, Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 2007, 128, 1077–1088. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Christensen, J.; Agger, K.; Cloos, P.A.; Pasini, D.; Rose, S.; Sennels, L.; Rappsilber, J.; Hansen, K.H.; Salcini, A.E.; Helin, K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 2007, 128, 1063–1076. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Qi, S.; Ngwa, C.; Al Mamun, A.; Romana, S.; Wu, T.; Marrelli, S.P.; Arnold, A.P.; McCullough, L.D.; Liu, F. X, but not Y, Chromosomal Complement Contributes to Stroke Sensitivity in Aged Animals. Transl. Stroke Res. 2022. [Google Scholar] [CrossRef]
  155. Qi, S.; Al Mamun, A.; Ngwa, C.; Romana, S.; Ritzel, R.; Arnold, A.P.; McCullough, L.D.; Liu, F. X chromosome escapee genes are involved in ischemic sexual dimorphism through epigenetic modification of inflammatory signals. J. Neuroinflamm. 2021, 18, 70. [Google Scholar] [CrossRef]
  156. Lisabeth, L.; Bushnell, C. Stroke risk in women: The role of menopause and hormone therapy. Lancet Neurol. 2012, 11, 82–91. [Google Scholar] [CrossRef] [Green Version]
  157. Itoh, Y.; Golden, L.C.; Itoh, N.; Matsukawa, M.A.; Ren, E.; Tse, V.; Arnold, A.P.; Voskuhl, R.R. The X-linked histone demethylase Kdm6a in CD4+ T lymphocytes modulates autoimmunity. J. Clin. Investig. 2019, 129, 3852–3863. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Outchkourov, N.S.; Muino, J.M.; Kaufmann, K.; van Ijcken, W.F.; Groot Koerkamp, M.J.; van Leenen, D.; de Graaf, P.; Holstege, F.C.; Grosveld, F.G.; Timmers, H.T. Balancing of histone H3K4 methylation states by the Kdm5c/SMCX histone demethylase modulates promoter and enhancer function. Cell Rep. 2013, 3, 1071–1079. [Google Scholar] [CrossRef] [Green Version]
  159. Wei, G.; Deng, X.; Agarwal, S.; Iwase, S.; Disteche, C.; Xu, J. Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells. J. Mol. Neurosci. 2016, 60, 33–45. [Google Scholar] [CrossRef] [Green Version]
  160. Swahari, V.; West, A.E. Histone demethylases in neuronal differentiation, plasticity, and disease. Curr. Opin. Neurobiol. 2019, 59, 9–15. [Google Scholar] [CrossRef]
  161. Hatch, H.A.M.; Secombe, J. Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome. FEBS J. 2021. [Google Scholar] [CrossRef]
  162. Vallianatos, C.N.; Raines, B.; Porter, R.S.; Bonefas, K.M.; Wu, M.C.; Garay, P.M.; Collette, K.M.; Seo, Y.A.; Dou, Y.; Keegan, C.E.; et al. Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation. Commun. Biol. 2020, 3, 278. [Google Scholar] [CrossRef] [PubMed]
  163. Jensen, L.R.; Amende, M.; Gurok, U.; Moser, B.; Gimmel, V.; Tzschach, A.; Janecke, A.R.; Tariverdian, G.; Chelly, J.; Fryns, J.P.; et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am. J. Hum. Genet. 2005, 76, 227–236. [Google Scholar] [CrossRef] [Green Version]
  164. Wu, P.M.; Yu, W.H.; Chiang, C.W.; Wu, C.Y.; Chen, J.S.; Tu, Y.F. Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability. Neurol. Genet. 2022, 8, e646. [Google Scholar] [CrossRef] [PubMed]
  165. Goncalves, T.F.; Goncalves, A.P.; Fintelman Rodrigues, N.; dos Santos, J.M.; Pimentel, M.M.; Santos-Reboucas, C.B. KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature. Eur. J. Med. Genet. 2014, 57, 138–144. [Google Scholar] [CrossRef] [PubMed]
  166. Abdelhaleem, M. RNA helicases: Regulators of differentiation. Clin. Biochem. 2005, 38, 499–503. [Google Scholar] [CrossRef]
  167. Garbelli, A.; Beermann, S.; Di Cicco, G.; Dietrich, U.; Maga, G. A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication. PLoS ONE 2011, 6, e19810. [Google Scholar] [CrossRef]
  168. Cruciat, C.M.; Dolde, C.; de Groot, R.E.; Ohkawara, B.; Reinhard, C.; Korswagen, H.C.; Niehrs, C. RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-beta-catenin signaling. Science 2013, 339, 1436–1441. [Google Scholar] [CrossRef]
  169. Tang, L.; Levy, T.; Guillory, S.; Halpern, D.; Zweifach, J.; Giserman-Kiss, I.; Foss-Feig, J.H.; Frank, Y.; Lozano, R.; Belani, P.; et al. Prospective and detailed behavioral phenotyping in DDX3X syndrome. Mol. Autism 2021, 12, 36. [Google Scholar] [CrossRef] [PubMed]
  170. Ruzzo, E.K.; Perez-Cano, L.; Jung, J.Y.; Wang, L.K.; Kashef-Haghighi, D.; Hartl, C.; Singh, C.; Xu, J.; Hoekstra, J.N.; Leventhal, O.; et al. Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell 2019, 178, 850–866.e26. [Google Scholar] [CrossRef] [Green Version]
  171. Kellaris, G.; Khan, K.; Baig, S.M.; Tsai, I.C.; Zamora, F.M.; Ruggieri, P.; Natowicz, M.R.; Katsanis, N. A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features. Hum. Genom. 2018, 12, 11. [Google Scholar] [CrossRef]
  172. Nicola, P.; Blackburn, P.R.; Rasmussen, K.J.; Bertsch, N.L.; Klee, E.W.; Hasadsri, L.; Pichurin, P.N.; Rankin, J.; Raymond, F.L.; Study, D.D.D.; et al. De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability. Am. J. Med. Genet. A 2019, 179, 570–578. [Google Scholar] [CrossRef] [PubMed]
  173. Hoye, M.L.; Calviello, L.; Poff, A.J.; Ejimogu, N.E.; Newman, C.R.; Montgomery, M.D.; Ou, J.; Floor, S.N.; Silver, D.L. Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model. eLife 2022, 11, e78203. [Google Scholar] [CrossRef] [PubMed]
  174. Patmore, D.M.; Jassim, A.; Nathan, E.; Gilbertson, R.J.; Tahan, D.; Hoffmann, N.; Tong, Y.; Smith, K.S.; Kanneganti, T.D.; Suzuki, H.; et al. DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma. Dev. Cell 2020, 54, 455–470.e5. [Google Scholar] [CrossRef] [PubMed]
  175. Szappanos, D.; Tschismarov, R.; Perlot, T.; Westermayer, S.; Fischer, K.; Platanitis, E.; Kallinger, F.; Novatchkova, M.; Lassnig, C.; Muller, M.; et al. The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity. PLoS Pathog. 2018, 14, e1007397. [Google Scholar] [CrossRef] [Green Version]
  176. Lennox, A.L.; Hoye, M.L.; Jiang, R.; Johnson-Kerner, B.L.; Suit, L.A.; Venkataramanan, S.; Sheehan, C.J.; Alsina, F.C.; Fregeau, B.; Aldinger, K.A.; et al. Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron 2020, 106, 404–420.e8. [Google Scholar] [CrossRef]
  177. Bellott, D.W.; Skaletsky, H.; Pyntikova, T.; Mardis, E.R.; Graves, T.; Kremitzki, C.; Brown, L.G.; Rozen, S.; Warren, W.C.; Wilson, R.K.; et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 2010, 466, 612–616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Skaletsky, H.; Kuroda-Kawaguchi, T.; Minx, P.J.; Cordum, H.S.; Hillier, L.; Brown, L.G.; Repping, S.; Pyntikova, T.; Ali, J.; Bieri, T.; et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003, 423, 825–837. [Google Scholar] [CrossRef] [Green Version]
  179. Mueller, J.L.; Skaletsky, H.; Brown, L.G.; Zaghlul, S.; Rock, S.; Graves, T.; Auger, K.; Warren, W.C.; Wilson, R.K.; Page, D.C. Independent specialization of the human and mouse X chromosomes for the male germ line. Nat. Genet. 2013, 45, 1083–1087. [Google Scholar] [CrossRef]
  180. Ross, J.L.; Bloy, L.; Roberts, T.P.L.; Miller, J.; Xing, C.; Silverman, L.A.; Zinn, A.R. Y chromosome gene copy number and lack of autism phenotype in a male with an isodicentric Y chromosome and absent NLGN4Y expression. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2019, 180, 471–482. [Google Scholar] [CrossRef] [PubMed]
  181. Maier, M.C.; McInerney, M.A.; Graves, J.A.M.; Charchar, F.J. Noncoding Genes on Sex Chromosomes and Their Function in Sex Determination, Dosage Compensation, Male Traits, and Diseases. Sex Dev. 2021, 15, 432–440. [Google Scholar] [CrossRef]
  182. Johansson, M.M.; Pottmeier, P.; Suciu, P.; Ahmad, T.; Zaghlool, A.; Halvardson, J.; Darj, E.; Feuk, L.; Peuckert, C.; Jazin, E. Novel Y-Chromosome Long Non-Coding RNAs Expressed in Human Male CNS During Early Development. Front. Genet. 2019, 10, 891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. De Vries, G.J. Minireview: Sex differences in adult and developing brains: Compensation, compensation, compensation. Endocrinology 2004, 145, 1063–1068. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. McCarthy, M.M.; Arnold, A.P. Reframing sexual differentiation of the brain. Nat. Neurosci. 2011, 14, 677–683. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Arnold, A.P. Rethinking sex determination of non-gonadal tissues. Curr. Top. Dev. Biol. 2019, 134, 289–315. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Four Core Genotypes (FCG) transgenic mouse model. XYSry mice carry two mutations that allowed to unlink the inheritance of the testis-determining Sry gene from that of the Y chromosome: (1) deletion of Sry from the Y chromosome, generating a “Y minus” or “Y”; (2) reinsertion of Sry into chromosome 3 (Chr3). Breeding XYSry with XX mice makes it possible to obtain four different genotypes: XY and XX gonadal females (mice carrying ovaries), XYSry and XXSry gonadal males (mice carrying testes). Comparison of a variable among the four genotypes allows independent assessment of the effects given by sex hormones (gonadal females vs. gonadal males), sex chromosome complement (XY vs. XX) or the interaction between these two factors (e.g., when a particular combination of gonadal type and sex chromosomes differs from the other three genotypes). ♀: gonadal female; ♂: gonadal male. Created with (accessed on 17 September 2022).
Figure 1. Four Core Genotypes (FCG) transgenic mouse model. XYSry mice carry two mutations that allowed to unlink the inheritance of the testis-determining Sry gene from that of the Y chromosome: (1) deletion of Sry from the Y chromosome, generating a “Y minus” or “Y”; (2) reinsertion of Sry into chromosome 3 (Chr3). Breeding XYSry with XX mice makes it possible to obtain four different genotypes: XY and XX gonadal females (mice carrying ovaries), XYSry and XXSry gonadal males (mice carrying testes). Comparison of a variable among the four genotypes allows independent assessment of the effects given by sex hormones (gonadal females vs. gonadal males), sex chromosome complement (XY vs. XX) or the interaction between these two factors (e.g., when a particular combination of gonadal type and sex chromosomes differs from the other three genotypes). ♀: gonadal female; ♂: gonadal male. Created with (accessed on 17 September 2022).
Ijms 23 12288 g001
Figure 2. X and Y chromosomes and mechanisms of sexual differentiation. Representations of the human X and Y chromosomes (generalizable to all eutherian mammals) are presented in the center, showing the pseudoautosomal regions (PAR1 and PAR2) at the distal ends, the non-PAR of the X, the male specific region of the Y (MSY) and the Sry gene position. Five mechanisms of sexual differentiation generated by inequalities in genetic content, expression and inheritance of X and Y are shown (discussion in text). Xa: active X; Xi: inactive X; XCI: X chromosome inactivation; Xm: maternal X; Xp: paternal X. Created with (accessed on 17 September 2022).
Figure 2. X and Y chromosomes and mechanisms of sexual differentiation. Representations of the human X and Y chromosomes (generalizable to all eutherian mammals) are presented in the center, showing the pseudoautosomal regions (PAR1 and PAR2) at the distal ends, the non-PAR of the X, the male specific region of the Y (MSY) and the Sry gene position. Five mechanisms of sexual differentiation generated by inequalities in genetic content, expression and inheritance of X and Y are shown (discussion in text). Xa: active X; Xi: inactive X; XCI: X chromosome inactivation; Xm: maternal X; Xp: paternal X. Created with (accessed on 17 September 2022).
Ijms 23 12288 g002
Table 1. X- and Y-linked genes involved or potentially involved in brain sexual differentiation and their main functions. Source: Gene Ontology (GO) database (accessed on 8 October 2022).
Table 1. X- and Y-linked genes involved or potentially involved in brain sexual differentiation and their main functions. Source: Gene Ontology (GO) database (accessed on 8 October 2022).
ChrGene (GO Database)
YSrysex determining region of Chr YDNA-binding transcription factor activity
Kdm6c-Utyhistone demethylase UTYHistone demethylase activity
Kdm5dlysine (K)-specific demethylase 5DHistone demethylase activity
Ddx3yDEAD box helicase 3, Y-linkedATP-dependent RNA helicase dbp3
Usp9yubiquitin specific peptidase 9, Y chromosomeCysteine-type deubiquitinase activity
Eif2s3yeukaryotic translation initiation factor 2, subunit 3, structural gene Y-linkedEukaryotic translation initiation factor 2 subunit 3 family member
Nlgn4yneuroligin-4, Y-linkedCell adhesion molecule
XKdm6a-Utxlysine (K)-specific demethylase 6AHistone demethylase activity
Kdm5clysine (K)-specific demethylase 5CLysine-specific demethylase
Ddx3xDEAD box helicase 3, X-linkedATP-dependent RNA helicase dbp3
Usp9xubiquitin specific peptidase 9, X chromosomeUbiquitin carboxyl-terminal hydrolase
Eif2s3xeukaryotic translation initiation factor 2, subunit 3, structural gene X-linkedEukaryotic translation initiation factor 2 subunit 3 family member
Mecp2methyl CpG binding protein 2DNA binding
Hdac8histone deacetylase 8Histone deacetylase activity
Morf4l2mortality factor 4 like 2Histone acetylation
Msl3MSL3 like 2Histone acetylation
Phf6PHD finger protein 6DNA metabolism protein
Fmr1fragile X messenger ribonucleoprotein 1Regulation of alternative mRNA splicing
Mid1midline 1E3 ubiquitin-protein ligase trim36-related
OgtO-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyl transferase)DNA binding
SypsynaptophysinLipid binding
Tmem47transmembrane protein 47Plasma membrane
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Cabrera Zapata, L.E.; Garcia-Segura, L.M.; Cambiasso, M.J.; Arevalo, M.A. Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain. Int. J. Mol. Sci. 2022, 23, 12288.

AMA Style

Cabrera Zapata LE, Garcia-Segura LM, Cambiasso MJ, Arevalo MA. Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain. International Journal of Molecular Sciences. 2022; 23(20):12288.

Chicago/Turabian Style

Cabrera Zapata, Lucas E., Luis Miguel Garcia-Segura, María Julia Cambiasso, and Maria Angeles Arevalo. 2022. "Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain" International Journal of Molecular Sciences 23, no. 20: 12288.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop