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Cells
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Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction
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Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Reproductive Cells and Development".

Deadline for manuscript submissions: 31 December 2025 | Viewed by 7596

Special Issue Editors

Dr. Zhengui Zheng

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Guest Editor
Department of Physiology, Southern Illinois University Carbondale, Carbondale, IL 62901, USA
Interests: sexually dimorphic development of external genitalia; sexually dimorphic limb and brain development and behavior; role of environmental endocrine disrupting chemicals on reproductive organ development
Dr. Brent M. Bany

E-Mail Website
Guest Editor
Department of Physiology, Southern Illinois University Carbondale, Carbondale, IL 62901, USA
Interests: development of the decidua during early pregnancy; mechanism of transdifferentiation of rodent and human endometrial fibroblasts into decidual cells; interactions between the conceptus and components of the endometrium (immune, vascular endothelial, decidual cells) during implantation and placental development
Dr. Liang Ma

E-Mail Website
Guest Editor
Department of Medicine, Division of Dermatology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
Interests: the development and function of the female reproductive tract; transcription factors regulating uterine epithelial differentiation and uterine decidualization; genetic mechanism of external genital development; spermatogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

All living organisms must reproduce in some way. In mammals, the reproductive process includes the formation and maturation of the sperm (males) and eggs (females), fertilization, implantation, and embryonic/placental/fetal development, parturition and lactation. The molecular and cellular mechanisms of these processes are largely unknown. The major organs of the reproductive system include external genitalia (penis and vulva) and some internal organs, including the gonads (testes and ovaries), which produce gametes. The cellular and molecular mechanisms underlying these developmental and reproductive organ functions are limited in many areas. Further, genetic factors, hormones and environmental endocrine-disrupting chemicals all have major impacts on reproduction, and human reproductive disorders are very common and widespread. It is essential to study the cellular and molecular mechanisms of not only the reproductive processes of reproductive organs, but also their development. Against this background, this Special Issue aims to provide an overview of advances in reproduction, with a particular focus on cellular and molecular mechanisms underlying reproductive organ development and their reproductive processes required for the successful procreation of mammalian species. Research articles and reviews summarizing the state of the art on special topics in this broad area are welcome. Potential topics include, but are not limited to, mechanisms of reproductive organ formation, sexual differentiation and function.

Furthermore, genetic and/or hormonal control of reproductive organ development, sexual differentiation, and function, fertilization, implantation, placentation, parturition and lactation are also of relevance. This can include, but is not limited to, studies linking molecular mechanisms to reproductive organ-related human disease, and also studies that include whole-genome genetic or epigenomic analyses.

Dr. Zhengui Zheng
Dr. Brent M. Bany
Dr. Liang Ma
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • reproductive organ development
  • sexual differentiation
  • reproductive tract function
  • fertilization
  • implantation
  • placentation
  • parturition
  • lactation

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Published Papers (6 papers)

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Research

23 pages, 2766 KiB  
Article
Prolactin Mediates Distinct Time Course Regulation of Tyrosine Hydroxylase Phosphorylation and Gene Expression in Tuberoinfundibular Dopaminergic Neurons of Female Rats
by Philip J. Jensik and Lydia A. Arbogast
Cells 2025, 14(9), 642; https://doi.org/10.3390/cells14090642 (registering DOI) - 27 Apr 2025
Viewed by 112
Abstract
Prolactin (PRL) regulates its own secretion by short-loop feedback to tuberoinfundibular dopaminergic (TIDA) neurons. PRL-induced cellular mechanisms in the regulation of tyrosine hydroxylase (TH) are not completely understood. The objectives were to (1) examine PRL-induced, time-dependent hypothalamic changes in JAK2-STAT5B signaling, TH activity, [...] Read more.
Prolactin (PRL) regulates its own secretion by short-loop feedback to tuberoinfundibular dopaminergic (TIDA) neurons. PRL-induced cellular mechanisms in the regulation of tyrosine hydroxylase (TH) are not completely understood. The objectives were to (1) examine PRL-induced, time-dependent hypothalamic changes in JAK2-STAT5B signaling, TH activity, TH phosphorylation state and Th mRNA levels, and (2) evaluate direct influences of PRLR-STAT5B signaling on Th promoter activity. Ovariectomized rats were administered ovine PRL. JAK2 and STAT5 phosphorylation in the mediobasal hypothalamus peaked at 15 and 30–60 min, respectively. TH Ser40 phosphorylation in the median eminence was increased between 2 and 72 h, correlating with increased dihydroxyphenylalanine (DOPA) accumulation. Th mRNA levels in TIDA neurons were unchanged up to 72 h but elevated by 7 days. PRL did not alter Th promoter activity in CAD cells, and STAT5B did not bind three putative Gamma Interferon Activation Sites (GAS) elements. We conclude that PRL initiates an integrated cascade of cellular mechanisms in TIDA neurons, including JAK2-STAT5B activation, TH Ser40 phosphorylation coupled to increased TH activity, followed by a delayed rise in Th gene expression. PRL-induced changes in Th gene expression are not the result of STAT5-mediated transactivation but likely result from enduring changes in TIDA neuronal activity. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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19 pages, 5886 KiB  
Article
DNA Methylation Mediates the Transcription of STAT4 to Regulate KISS1 During Follicular Development
by Danxia Chen, Ming Fang, Enyuan Huang, Hongyan Quan, Liuhong Zhang, Yingting He, Xiaofeng Zhou, Bin Ma, Xiaolong Yuan and Jiaqi Li
Cells 2025, 14(7), 523; https://doi.org/10.3390/cells14070523 - 1 Apr 2025
Viewed by 303
Abstract
Maturation of follicles is the primary condition for the initiation of puberty, and excessive apoptosis of granulosa cells (GCs) will hinder the normal development of follicles in pigs. Signal Transducer and Activator of Transcription 4 (STAT4) plays an important role in [...] Read more.
Maturation of follicles is the primary condition for the initiation of puberty, and excessive apoptosis of granulosa cells (GCs) will hinder the normal development of follicles in pigs. Signal Transducer and Activator of Transcription 4 (STAT4) plays an important role in cell proliferation and apoptosis. However, the mechanism of DNA methylation regulating STAT4 transcription and affecting follicle development in pigs remains unclear. To resolve this problem, we constructed a STAT4 overexpression vector and interference fragment to explore the effects of STAT4 on GC function and investigate the effects of changes in methylation status of the STAT4 promoter region on cell function and kisspeptin-1 (KISS1) expression, as well as the STAT4 effects on the development of the follicles of pigs and mice in vitro. We found that the expression of STAT4 decreased, while DNA methylation of the STAT4 promoter region increased with the growth of the follicles. After overexpression of STAT4, the apoptosis of GCs was increased but the proliferation, cell cycle and estrogen secretion of GCs were inhibited. When GCs were treated with DNA methyltransferase inhibitor (5-Aza-CdR), the methylation of the STAT4 promoter region decreased, resulting in a significant increase in the expression of STAT4. Consequently, the expression of KISS1 was inhibited. At the same time, the expressions of genes related to cell proliferation, cell cycle and estrogen secretion signaling pathways decreased, while the expressions of genes related to the apoptosis signaling pathway increased. After infection with the STAT4 lentiviral vector (LV-STAT4) in follicles of mice, the expression of STAT4 in ovaries of mice significantly increased, and the expression of KISS1 was significantly decreased. The capillaries on the surface of follicles were constricted, the age of puberty onset in mice was delayed while the levels of GnRH, LH, FSH and E2 in serum were decreased. In conclusion, we found that reduced methylation status of the STAT4 promoter region promoted the transcription of STAT4 and then inhibited the expression of KISS1, as well as promoted the apoptosis of GCs and ultimately inhibited the normal development of follicles in mammals. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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16 pages, 2977 KiB  
Article
RHOX Homeobox Transcription Factor Regulation of Ins2 in Rodent Granulosa Cells
by Kanako Hayashi and James A. MacLean II
Cells 2025, 14(7), 478; https://doi.org/10.3390/cells14070478 - 22 Mar 2025
Viewed by 317
Abstract
The Rhox family of homeobox transcription factors comprises established regulators of gonad function, but their downstream targets have been relatively elusive, particularly in the female reproductive tract. Here, we characterize Ins2 as a downstream target of the two granulosa cell-specific factors, Rhox5 and [...] Read more.
The Rhox family of homeobox transcription factors comprises established regulators of gonad function, but their downstream targets have been relatively elusive, particularly in the female reproductive tract. Here, we characterize Ins2 as a downstream target of the two granulosa cell-specific factors, Rhox5 and Rhox8, in the ovary. While INS2 is classically produced by islet cells in the pancreas, we found that Ins2 gene expression is present in the mural granulosa cell layer of large antral follicles, and it was not significantly reduced in Rhox5-null mice. This was a surprising finding as we previously validated Ins2 as a direct target of RHOX5 in Sertoli cells, the male counterpart to granulosa cells that serves the germ cell nurse function in the testis. In the ovary, RHOX8 appears to be the major driver of Ins2 expression, as evidenced from the maximal activity of Ins2 promoter reporter plasmids when RHOX8 protein was active within granulosa cells in vitro and the downregulation of endogenous Ins2 in mice with the granulosa cell-specific knockdown of RHOX8 in vivo. RHOX5 induces Rhox8 expression in pre-antral granulosa cells and then becomes relatively silent in peri-ovulatory follicles. However, Rhox8 does not peak until after the ovulatory LH surge. The induction of Rhox8 by progesterone, after the normal window of RHOX5 has passed, may explain why Rhox5-null female mice display apparently normal fertility, if RHOX8 is capable of the redundant stimulation of target genes that are essential for ovulation. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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22 pages, 3161 KiB  
Article
The Long Non-Coding RNA Gene AC027288.3 Plays a Role in Human Endometrial Stromal Fibroblast Decidualization
by Rupak Thapa, Kevin Marmo, Liang Ma, Donald S. Torry and Brent M. Bany
Cells 2024, 13(9), 778; https://doi.org/10.3390/cells13090778 - 2 May 2024
Cited by 1 | Viewed by 2806
Abstract
During the secretory phase of the menstrual cycle, endometrial fibroblast cells begin to change into large epithelial-like cells called decidual cells in a process called decidualization. This differentiation continues more broadly in the endometrium and forms the decidual tissue during early pregnancy. The [...] Read more.
During the secretory phase of the menstrual cycle, endometrial fibroblast cells begin to change into large epithelial-like cells called decidual cells in a process called decidualization. This differentiation continues more broadly in the endometrium and forms the decidual tissue during early pregnancy. The cells undergoing decidualization as well as the resulting decidual cells, support successful implantation and placentation during early pregnancy. This study was carried out to identify new potentially important long non-coding RNA (lncRNA) genes that may play a role in human endometrial stromal fibroblast cells (hESF) undergoing decidualization in vitro, and several were found. The expression of nine was further characterized. One of these, AC027288.3, showed a dramatic increase in the expression of hESF cells undergoing decidualization. When AC027288.3 expression was targeted, the ability of the cells to undergo decidualization as determined by the expression of decidualization marker protein-coding genes was significantly altered. The most affected markers of decidualization whose expression was significantly reduced were FOXO1, FZD4, and INHBA. Therefore, AC027288.3 may be a major upstream regulator of the WNT-FOXO1 pathway and activin-SMAD3 pathways previously shown as critical for hESF decidualization. Finally, we explored possible regulators of AC027288.3 expression during human ESF decidualization. Expression was regulated by cAMP and progesterone. Our results suggest that AC027288.3 plays a role in hESF decidualization and identifies several other lncRNA genes that may also play a role. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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19 pages, 2196 KiB  
Article
HDAC1-Mediated lncRNA Stimulatory Factor of Follicular Development to Inhibit the Apoptosis of Granulosa Cells and Regulate Sexual Maturity through miR-202-3p-COX1 Axis
by Xiaofeng Zhou, Yingting He, Hongyan Quan, Xiangchun Pan, Yinqi Zhou, Zhe Zhang, Xiaolong Yuan and Jiaqi Li
Cells 2023, 12(23), 2734; https://doi.org/10.3390/cells12232734 - 29 Nov 2023
Cited by 3 | Viewed by 1667
Abstract
Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might serve as a potential therapeutic approach to regulate sexual maturity. However, the mechanisms that account for it remain to be further elucidated. [...] Read more.
Abnormal sexual maturity exhibits significant detrimental effects on adult health outcomes, and previous studies have indicated that targeting histone acetylation might serve as a potential therapeutic approach to regulate sexual maturity. However, the mechanisms that account for it remain to be further elucidated. Using the mouse model, we showed that Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, downregulated the protein level of Hdac1 in ovaries to promote the apoptosis of granulosa cells (GCs), and thus arrested follicular development and delayed sexual maturity. Using porcine GCs as a cell model, a novel sexual maturity-associated lncRNA, which was named as the stimulatory factor of follicular development (SFFD), transcribed from mitochondrion and mediated by HDAC1, was identified using RNA sequencing. Mechanistically, HDAC1 knockdown significantly reduced the H3K27ac level at the −953/−661 region of SFFD to epigenetically inhibit its transcription. SFFD knockdown released miR-202-3p to reduce the expression of cyclooxygenase 1 (COX1), an essential rate-limited enzyme involved in prostaglandin synthesis. This reduction inhibited the proliferation and secretion of 17β-estradiol (E2) while promoting the apoptosis of GCs. Consequently, follicular development was arrested and sexual maturity was delayed. Taken together, HDAC1 knockdown-mediated SFFD downregulation promoted the apoptosis of GCs through the miR-202-3p-COX1 axis and lead to delayed sexual maturity. Our findings reveal a novel regulatory network modulated by HDAC1, and HDAC1-mediated SFFD may be a promising new therapeutic target to treat delayed sexual maturity. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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12 pages, 4389 KiB  
Article
Lysophosphatidic Acid Signalling Regulates Human Sperm Viability via the Phosphoinositide 3-Kinase/AKT Pathway
by Hao-Yu Liao and Cristian O’Flaherty
Cells 2023, 12(17), 2196; https://doi.org/10.3390/cells12172196 - 2 Sep 2023
Cited by 4 | Viewed by 1870
Abstract
Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A2 (iPLA2) releases lysophospholipids such as LPA or arachidonic [...] Read more.
Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A2 (iPLA2) releases lysophospholipids such as LPA or arachidonic acid (AA) and that inhibiting PRDX6 iPLA2 activity impairs sperm cell viability. The exogenous addition of LPA bypassed the inhibition of PRDX6 iPLA2 activity and maintained the active phosphoinositide 3-kinase (PI3K)/AKT pathway. Here, we aimed to study PI3K/AKT pathway regulation via LPA signalling and protein kinases in maintaining sperm viability. The localization of LPARs in human spermatozoa was determined using immunocytochemistry, and P-PI3K and P-AKT substrate phosphorylations via immunoblotting. Sperm viability was determined using the hypo-osmotic swelling test. LPAR1, 3, 5 and 6 were located on the sperm plasma membrane. The inhibition of LPAR1-3 with Ki16425 promoted the impairment of sperm viability and decreased the phosphorylation of PI3K AKT substrates. Inhibitors of PKC, receptor-type PTK and PLC impaired sperm viability and the PI3K/AKT pathway. Adding 1-oleoyl-2-acetyl-snglycerol (OAG), a cell-permeable analog of diacylglycerol (DAG), prevented the loss of sperm viability and maintained the phosphorylation of PI3K. In conclusion, human sperm viability is supported by LPAR signalling and regulated by PLC, PKC and RT-PTK by maintaining phosphorylation levels of PI3K and AKT substrates. Full article
(This article belongs to the Special Issue Select Topics in Molecular and Cellular Mechanisms of Mammalian Reproduction)
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