Special Issue "Molecular and Cellular Mechanisms of Neocortical Circuit Formation"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 February 2022) | Viewed by 17358

Special Issue Editor

Prof. Mladen-Roko Rasin
E-Mail Website
Guest Editor
Department of Neuroscience and Cell Biology, Rutgers University, RWJ Medical School, 675 Hoes Lane West, R-343A, Piscataway, NJ 08854, USA
Interests: mRNA translation; ribosome; RNA binding protein; ribosomal protein; neuron; glia; synapse; stem cell; migration; axon; neocortex; dendrite; epilepsy; autism

Special Issue Information

Dear Colleagues,

This special issue will be an in-depth overview of our current knowledge of transcriptional and post-transcriptional processing in neurodevelopment. Each manuscript will describe a conceptual paradigm of brain development and the molecular and cellular mechanisms behind it, with focus on the neocortex. Special issue will start with manuscripts summarizing and discussing current developmental concepts about neocortical neural stem cells, migration, and post-migratory neuronal and glial development. This will be followed by current state of knowledge of transcriptional programs contributing to these events, which will be followed by manuscripts on the roles of post-transcriptional steps: RNA splicing, transport, decay, and translation. Final manuscripts will be related to neurodevelopmental disorders associated with the abnormal neocortical development.

Prof. Mladen-Roko Rasin
Guest Editor

Manuscript Submission Information

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Keywords

  • neural stem cells
  • RNA splicing
  • mRNA translation
  • neuron
  • glia
  • synapse
  • ribosome
  • RNA binding protein
  • ribosomal protein
  • radial glia
  • ventricular zone
  • glutamatergic
  • axon

Published Papers (12 papers)

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Research

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Article
Rab27a-Dependent Paracrine Communication Controls Dendritic Spine Formation and Sensory Responses in the Barrel Cortex
Cells 2021, 10(3), 622; https://doi.org/10.3390/cells10030622 - 11 Mar 2021
Cited by 2 | Viewed by 943
Abstract
Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that [...] Read more.
Rab27a is an evolutionarily conserved small GTPase that regulates vesicle trafficking, and copy number variants of RAB27a are associated with increased risk of autism. However, the function of Rab27a on brain development is unknown. Here, we identified a form of paracrine communication that regulates spine development between distinct populations of developing cortical neurons. In the developing somatosensory cortex of mice, we show that decreasing Rab27a levels in late-born pyramidal neurons destined for layer (L) 2/3 had no cell-autonomous effect on their synaptic integration but increased excitatory synaptic transmission onto L4 neurons that receive somatosensory information. This effect resulted in an increased number of L4 neurons activated by whisker stimulation in juvenile mice. In addition, we found that Rab27a, the level of which decreases as neurons mature, regulates the release of small extracellular vesicles (sEVs) in developing neurons in vitro and decreasing Rab27a levels led to the accumulation of CD63-positive vesicular compartments in L2/3 neurons in vivo. Together, our study reveals that Rab27a-mediated paracrine communication regulates the development of synaptic connectivity, ultimately tuning responses to sensory stimulation, possibly via controlling the release of sEVs. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Article
Adult Upper Cortical Layer Specific Transcription Factor CUX2 Is Expressed in Transient Subplate and Marginal Zone Neurons of the Developing Human Brain
Cells 2021, 10(2), 415; https://doi.org/10.3390/cells10020415 - 17 Feb 2021
Cited by 1 | Viewed by 1021
Abstract
Cut-Like Homeobox 2 (Cux2) is a transcription factor involved in dendrite and spine development, and synapse formation of projection neurons placed in mouse upper neocortical layers. Therefore, Cux2 is often used as an upper layer marker in the mouse brain. However, expression of [...] Read more.
Cut-Like Homeobox 2 (Cux2) is a transcription factor involved in dendrite and spine development, and synapse formation of projection neurons placed in mouse upper neocortical layers. Therefore, Cux2 is often used as an upper layer marker in the mouse brain. However, expression of its orthologue CUX2 remains unexplored in the human fetal neocortex. Here, we show that CUX2 protein is expressed in transient compartments of developing neocortical anlage during the main fetal phases of neocortical laminar development in human brain. During the early fetal phase when neurons of the upper cortical layers are still radially migrating to reach their final place in the cortical anlage, CUX2 was expressed in the marginal zone (MZ), deep cortical plate, and pre-subplate. During midgestation, CUX2 was still expressed in the migrating upper cortical neurons as well as in the subplate (SP) and MZ neurons. At the term age, CUX2 was expressed in the gyral white matter along with its expected expression in the upper layer neurons. In sum, CUX2 was expressed in migratory neurons of prospective superficial layers and in the diverse subpopulation of transient postmigratory SP and MZ neurons. Therefore, our findings indicate that CUX2 is a novel marker of distinct transient, but critical histogenetic events during corticogenesis. Given the Cux2 functions reported in animal models, our data further suggest that the expression of CUX2 in postmigratory SP and MZ neurons is associated with their unique dendritic and synaptogenesis characteristics. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Article
Extrinsic Regulators of mRNA Translation in Developing Brain: Story of WNTs
Cells 2021, 10(2), 253; https://doi.org/10.3390/cells10020253 - 28 Jan 2021
Cited by 2 | Viewed by 1006
Abstract
Extrinsic molecules such as morphogens can regulate timed mRNA translation events in developing neurons. In particular, Wingless-type MMTV integration site family, member 3 (Wnt3), was shown to regulate the translation of Foxp2 mRNA encoding a Forkhead transcription factor P2 in the neocortex. However, [...] Read more.
Extrinsic molecules such as morphogens can regulate timed mRNA translation events in developing neurons. In particular, Wingless-type MMTV integration site family, member 3 (Wnt3), was shown to regulate the translation of Foxp2 mRNA encoding a Forkhead transcription factor P2 in the neocortex. However, the Wnt receptor that possibly mediates these translation events remains unknown. Here, we report Frizzled member 7 (Fzd7) as the Wnt3 receptor that lays downstream in Wnt3-regulated mRNA translation. Fzd7 proteins co-localize with Wnt3 ligands in developing neocortices. In addition, the Fzd7 proteins overlap in layer-specific neuronal subpopulations expressing different transcription factors, Foxp1 and Foxp2. When Fzd7 was silenced, we found decreased Foxp2 protein expression and increased Foxp1 protein expression, respectively. The Fzd7 silencing also disrupted the migration of neocortical glutamatergic neurons. In contrast, Fzd7 overexpression reversed the pattern of migratory defects and Foxp protein expression that we found in the Fzd7 silencing. We further discovered that Fzd7 is required for Wnt3-induced Foxp2 mRNA translation. Surprisingly, we also determined that the Fzd7 suppression of Foxp1 protein expression is not Wnt3 dependent. In conclusion, it is exhibited that the interaction between Wnt3 and Fzd7 regulates neuronal identity and the Fzd7 receptor functions as a downstream factor in ligand Wnt3 signaling for mRNA translation. In particular, the Wnt3-Fzd7 signaling axis determines the deep layer Foxp2-expressing neurons of developing neocortices. Our findings also suggest that Fzd7 controls the balance of the expression for Foxp transcription factors in developing neocortical neurons. These discoveries are presented in our manuscript within a larger framework of this review on the role of extrinsic factors in regulating mRNA translation. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Article
Clonal Analysis of Gliogenesis in the Cerebral Cortex Reveals Stochastic Expansion of Glia and Cell Autonomous Responses to Egfr Dosage
Cells 2020, 9(12), 2662; https://doi.org/10.3390/cells9122662 - 11 Dec 2020
Cited by 7 | Viewed by 1574
Abstract
Development of the nervous system undergoes important transitions, including one from neurogenesis to gliogenesis which occurs late during embryonic gestation. Here we report on clonal analysis of gliogenesis in mice using Mosaic Analysis with Double Markers (MADM) with quantitative and computational methods. Results [...] Read more.
Development of the nervous system undergoes important transitions, including one from neurogenesis to gliogenesis which occurs late during embryonic gestation. Here we report on clonal analysis of gliogenesis in mice using Mosaic Analysis with Double Markers (MADM) with quantitative and computational methods. Results reveal that developmental gliogenesis in the cerebral cortex occurs in a fraction of earlier neurogenic clones, accelerating around E16.5, and giving rise to both astrocytes and oligodendrocytes. Moreover, MADM-based genetic deletion of the epidermal growth factor receptor (Egfr) in gliogenic clones revealed that Egfr is cell autonomously required for gliogenesis in the mouse dorsolateral cortices. A broad range in the proliferation capacity, symmetry of clones, and competitive advantage of MADM cells was evident in clones that contained one cellular lineage with double dosage of Egfr relative to their environment, while their sibling Egfr-null cells failed to generate glia. Remarkably, the total numbers of glia in MADM clones balance out regardless of significant alterations in clonal symmetries. The variability in glial clones shows stochastic patterns that we define mathematically, which are different from the deterministic patterns in neuronal clones. This study sets a foundation for studying the biological significance of stochastic and deterministic clonal principles underlying tissue development, and identifying mechanisms that differentiate between neurogenesis and gliogenesis. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review

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Review
Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates
Cells 2021, 10(4), 914; https://doi.org/10.3390/cells10040914 - 16 Apr 2021
Viewed by 985
Abstract
The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can [...] Read more.
The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
Recurrent Implication of Striatal Cholinergic Interneurons in a Range of Neurodevelopmental, Neurodegenerative, and Neuropsychiatric Disorders
Cells 2021, 10(4), 907; https://doi.org/10.3390/cells10040907 - 15 Apr 2021
Cited by 7 | Viewed by 1475
Abstract
Cholinergic interneurons are “gatekeepers” for striatal circuitry and play pivotal roles in attention, goal-directed actions, habit formation, and behavioral flexibility. Accordingly, perturbations to striatal cholinergic interneurons have been associated with many neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The role of acetylcholine in many of [...] Read more.
Cholinergic interneurons are “gatekeepers” for striatal circuitry and play pivotal roles in attention, goal-directed actions, habit formation, and behavioral flexibility. Accordingly, perturbations to striatal cholinergic interneurons have been associated with many neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The role of acetylcholine in many of these disorders is well known, but the use of drugs targeting cholinergic systems fell out of favor due to adverse side effects and the introduction of other broadly acting compounds. However, in response to recent findings, re-examining the mechanisms of cholinergic interneuron dysfunction may reveal key insights into underlying pathogeneses. Here, we provide an update on striatal cholinergic interneuron function, connectivity, and their putative involvement in several disorders. In doing so, we aim to spotlight recurring physiological themes, circuits, and mechanisms that can be investigated in future studies using new tools and approaches. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
White Matter Interstitial Neurons in the Adult Human Brain: 3% of Cortical Neurons in Quest for Recognition
Cells 2021, 10(1), 190; https://doi.org/10.3390/cells10010190 - 19 Jan 2021
Cited by 7 | Viewed by 1285
Abstract
White matter interstitial neurons (WMIN) are a subset of cortical neurons located in the subcortical white matter. Although they were fist described over 150 years ago, they are still largely unexplored and often considered a small, functionally insignificant neuronal population. WMIN are adult [...] Read more.
White matter interstitial neurons (WMIN) are a subset of cortical neurons located in the subcortical white matter. Although they were fist described over 150 years ago, they are still largely unexplored and often considered a small, functionally insignificant neuronal population. WMIN are adult remnants of neurons located in the transient fetal subplate zone (SP). Following development, some of the SP neurons undergo apoptosis, and the remaining neurons are incorporated in the adult white matter as WMIN. In the adult human brain, WMIN are quite a large population of neurons comprising at least 3% of all cortical neurons (between 600 and 1100 million neurons). They include many of the morphological neuronal types that can be found in the overlying cerebral cortex. Furthermore, the phenotypic and molecular diversity of WMIN is similar to that of the overlying cortical neurons, expressing many glutamatergic and GABAergic biomarkers. WMIN are often considered a functionally unimportant subset of neurons. However, upon closer inspection of the scientific literature, it has been shown that WMIN are integrated in the cortical circuitry and that they exhibit diverse electrophysiological properties, send and receive axons from the cortex, and have active synaptic contacts. Based on these data, we are able to enumerate some of the potential WMIN roles, such as the control of the cerebral blood flow, sleep regulation, and the control of information flow through the cerebral cortex. Also, there is a number of studies indicating the involvement of WMIN in the pathophysiology of many brain disorders such as epilepsy, schizophrenia, Alzheimer’s disease, etc. All of these data indicate that WMIN are a large population with an important function in the adult brain. Further investigation of WMIN could provide us with novel data crucial for an improved elucidation of the pathophysiology of many brain disorders. In this review, we provide an overview of the current WMIN literature, with an emphasis on studies conducted on the human brain. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
Stick around: Cell–Cell Adhesion Molecules during Neocortical Development
Cells 2021, 10(1), 118; https://doi.org/10.3390/cells10010118 - 10 Jan 2021
Cited by 5 | Viewed by 1356
Abstract
The neocortex is an exquisitely organized structure achieved through complex cellular processes from the generation of neural cells to their integration into cortical circuits after complex migration processes. During this long journey, neural cells need to establish and release adhesive interactions through cell [...] Read more.
The neocortex is an exquisitely organized structure achieved through complex cellular processes from the generation of neural cells to their integration into cortical circuits after complex migration processes. During this long journey, neural cells need to establish and release adhesive interactions through cell surface receptors known as cell adhesion molecules (CAMs). Several types of CAMs have been described regulating different aspects of neurodevelopment. Whereas some of them mediate interactions with the extracellular matrix, others allow contact with additional cells. In this review, we will focus on the role of two important families of cell–cell adhesion molecules (C-CAMs), classical cadherins and nectins, as well as in their effectors, in the control of fundamental processes related with corticogenesis, with special attention in the cooperative actions among the two families of C-CAMs. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
New Molecular Players in the Development of Callosal Projections
Cells 2021, 10(1), 29; https://doi.org/10.3390/cells10010029 - 26 Dec 2020
Cited by 3 | Viewed by 1249
Abstract
Cortical development in humans is a long and ongoing process that continuously modifies the neural circuitry into adolescence. This is well represented by the dynamic maturation of the corpus callosum, the largest white matter tract in the brain. Callosal projection neurons whose long-range [...] Read more.
Cortical development in humans is a long and ongoing process that continuously modifies the neural circuitry into adolescence. This is well represented by the dynamic maturation of the corpus callosum, the largest white matter tract in the brain. Callosal projection neurons whose long-range axons form the main component of the corpus callosum are evolved relatively recently with a substantial, disproportionate increase in numbers in humans. Though the anatomy of the corpus callosum and cellular processes in its development have been intensively studied by experts in a variety of fields over several decades, the whole picture of its development, in particular, the molecular controls over the development of callosal projections, still has many missing pieces. This review highlights the most recent progress on the understanding of corpus callosum formation with a special emphasis on the novel molecular players in the development of axonal projections in the corpus callosum. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
Ariadne’s Thread in the Developing Cerebral Cortex: Mechanisms Enabling the Guiding Role of the Radial Glia Basal Process during Neuron Migration
Cells 2021, 10(1), 3; https://doi.org/10.3390/cells10010003 - 22 Dec 2020
Viewed by 1863
Abstract
Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating [...] Read more.
Radial neuron migration in the developing cerebral cortex is a complex journey, starting in the germinal zones and ending in the cortical plate. In mice, migratory distances can reach several hundreds of microns, or millimeters in humans. Along the migratory path, radially migrating neurons slither through cellularly dense and complex territories before they reach their final destination in the cortical plate. This task is facilitated by radial glia, the neural stem cells of the developing cortex. Indeed, radial glia have a unique bipolar morphology, enabling them to serve as guides for neuronal migration. The key guiding structure of radial glia is the basal process, which traverses the entire thickness of the developing cortex. Neurons recognize the basal process as their guide and maintain physical interactions with this structure until the end of migration. Thus, the radial glia basal process plays a key role during radial migration. In this review, we highlight the pathways enabling neuron-basal process interactions during migration, as well as the known mechanisms regulating the morphology of the radial glia basal process. Throughout, we describe how dysregulation of these interactions and of basal process morphology can have profound effects on cortical development, and therefore lead to neurodevelopmental diseases. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
Linking Autism Risk Genes to Disruption of Cortical Development
Cells 2020, 9(11), 2500; https://doi.org/10.3390/cells9112500 - 18 Nov 2020
Cited by 8 | Viewed by 2560
Abstract
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress [...] Read more.
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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Review
Molecular Evolution, Neurodevelopmental Roles and Clinical Significance of HECT-Type UBE3 E3 Ubiquitin Ligases
Cells 2020, 9(11), 2455; https://doi.org/10.3390/cells9112455 - 10 Nov 2020
Cited by 4 | Viewed by 1308
Abstract
Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is just the tip of an iceberg. The divergence of enzymatic executors of ubiquitination led to some 600–700 E3 ubiquitin ligases [...] Read more.
Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is just the tip of an iceberg. The divergence of enzymatic executors of ubiquitination led to some 600–700 E3 ubiquitin ligases embedded in the human genome. Notably, mutations in around 13% of these genes are causative of severe neurological diseases. Despite this, molecular and cellular context of ubiquitination remains poorly characterized, especially in the developing brain. In this review article, we summarize recent findings on brain-expressed HECT-type E3 UBE3 ligases and their murine orthologues, comprising Angelman syndrome UBE3A, Kaufman oculocerebrofacial syndrome UBE3B and autism spectrum disorder-associated UBE3C. We summarize evolutionary emergence of three UBE3 genes, the biochemistry of UBE3 enzymes, their biology and clinical relevance in brain disorders. Particularly, we highlight that uninterrupted action of UBE3 ligases is a sine qua non for cortical circuit assembly and higher cognitive functions of the neocortex. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neocortical Circuit Formation)
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