Talk:Genital System Development
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Cite this page: Hill, M.A. (2024, April 23) Embryology Genital System Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Genital_System_Development |
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Note - This sub-heading shows an automated computer PubMed search using the listed sub-heading term. References appear in this list based upon the date of the actual page viewing. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. In comparison, references listed on the content page and discussion page (under the publication year sub-headings) do include editorial selection based upon relevance and availability. (More? Pubmed Most Recent)
Genital Development
<pubmed limit=5>Genital Development</pubmed>
2018
Royal Hospital for Women - Reproductive Medicine Seminar 2018
Dr Rachael Rodgers Male and female reproductive/urogenital systems, breast, thyroid, adrenals, kidneys, hypothalamus and pituitary, it would be perfect.
It’s Rachael Rodgers here. I’m one of the fertility fellow / gynaecologists at the Royal Hospital for Women. I’m writing to ask if it would be possible for you to give a presentation on embryology at one of the teaching sessions we hold in the Reproductive Medicine department. Every second Tuesday morning, we have a teaching session in the Reproductive Medicine department that runs from 8-9am. The specialists, fellows, registrars, junior doctors and nurses from the Royal Hospital for Women attend, as well as some scientists from UNSW.
We would be very grateful if you would be able to give a lecture, Professor Ledger indicated to me that he thought you would be excellent. Specifically we were hoping that you could give a presentation on the embryonic development of the male and female reproductive structures (urogenital system primarily, also a brief mention of related structures such as the breast, urinary system, thyroid and adrenals if time permits). Our teaching restarts on 13th Feb, and then is held every second week after this.
Kind regards,
Dr Rachael Rodgers
BA, BSc, MBBS (Hons), MScMed (RHHG), FRANZCOG CREI Fellow / Gynaecology Senior Registrar Royal Hospital for Women Department of Reproductive Medicine Barker St, Randwick 2031 Phone: +61 402 136 657
2017
Sex determination and maintenance: the role of DMRT1 and FOXL2
Huang S1, Ye L2, Chen H2.
Asian J Androl. 2017 Nov-Dec;19(6):619-624. doi: 10.4103/1008-682X.194420.
Abstract
In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 (Dmrt1) and forkhead box L2 (Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility. PMID: 28091399 PMCID: PMC5676419 DOI: 10.4103/1008-682X.194420
Male
- Initial activation of SRY (Mouse - Wilms tumor 1 (Wt1), GATA binding protein 4 (Gata4), zinc fnger protein, fog family member 2 (Zfpm2), chromobox homolog 2 (Cbx2), mitogen-activated protein kinase 4 (Map3k4), and the insulin receptors.
- SRY activates SOX9
- SOX9 expression requires positive regulatory loop with fibroblast growth factor 9 (Fgf9) and lipocalin-type prostaglandin D2 synthase (Ptgds) PTGDS is an enzyme that catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2).
- feed-forward regulatory loop between Sox9 and Fgf9 results in upregulation of Fgf9 expression and repression of a female promoting gene, wingless-related MMTV integration site 4 (Wnt4)
expressions of SOX9, FGF9, and PTGDS in bipotential embryonic genital ridges determine the fate of Sertoli cells.
- mesonephric cell migration, testis cord formation, testis-speci c vascularization, and myoid and Leydig cell di erentiation.
- late stages of testicular development, including WT1, steroidogenic factor 1 (SF1), GATA4, DMRT1, desert hedgehog (DHH), and platelet-derived growth factor (PDGF).
- DMRT proteins are transcription factors that share a DNA-binding domain that is similar to a zinc nger, called the DM domain.
- DMRT1 is predominantly expressed in Sertoli cells, whereas at later gestation (GW 22-40), childhood, and postpuberty, DMRT1 is most abundant in spermatogonia.
Retinoic acid (RA) signaling between Sertoli and germ cells is essential for adult mammalian spermatogenesis.
Male, the positive feedback regulatory loops (Sox9-Fgf9 and Sox9-Ptgds) not only reinforce the activation of the male signaling network but also inhibit the key members of the female network members (Wnt4, Rspo1, and Foxl2).
activation of female signaling molecules has negative e ects on the expression of male genes.
DMRT1 and FOXL2 maintain male and female gonadal sex phenotypes
Female
- essential ovary-specific factors exist (β-catenin, follistatin [Fst], FOXL2, R-spondin [RSPO1], and WNT4)
- germ cells, which enter meiosis and become primary oocytes in the developing ovary; the granulosa cells, which support germ cell development (analogous to Sertoli cells); and the theca cells, which produce steroid hormones (analogous to Leydig cells)
- duplications of the WNT4 gene in males or loss of functional mutations in females resulted in diverse sexual anomalies including cryptorchidism
- Wnt4 in the XX gonad is to inhibit important testis-specific processes, including migration of endothelial cells from the mesonephros39 and steroidogenesis, either by repressing Sf140 or precluding the recruitment of steroidogenic cell precursors.
- mutations in RSPO1, a ligand for canonical WNT signaling,41,42 resulted in female-to-male sex reversal
- RSPO1 suppresses the male pathway in the absence of SRY by activating WNT4 signaling.
- β-catenin is the common e ector of both RSPO1 and WNT4 signaling
- FOXL2 (mice) not be involved in early XX female-to-male sex reversal but is necessary for correct follicle development and female fertility maintenance in postnatal animals.
- FOXL2 directly repress the testis-specific enhancer of Sox9 through synergistic interaction with estrogen receptors-α and -β (ER-α-β)
- Foxl2 expression is necessary to actively suppress Sox9 expression in the ovary throughout life.
- sustained Foxl2 expression is necessary for repressing genetic reprogramming of the postnatal ovarian somatic cells to testicular cell types, and thus for the maintenance of the adult female phenotype
- Mutations in the FOXL2 gene in humans are associated with Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES), a condition that a ects development of the eyelids and premature ovarian failure in females
- mice Foxl2 was found to play a role in maintaining ovarian functions postnatally, FOXL2 is a bona fide female sex-determining gene in goat.
Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development
Clin Genet. 2017 Feb;91(2):143-156. doi: 10.1111/cge.12932.
Bashamboo A1, Eozenou C1, Rojo S1, McElreavey K1.
Abstract
Human sex determination (SD) involves complex mutually antagonistic genetic interactions of testis- and ovary-determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro-male and pro-female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double-repressive pathway. Here, we review genetic data generated through large-scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent NR5A1 p.R92W mutation associated with testis development in 46,XX children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of SD across species. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
KEYWORDS: NR5A1; cell-fate choice decisions; cellular models of human disease; disorders of sex development; gonadal dysgenesis; infertility; sex determination; testicular DSD PMID 27893151 DOI: 10.1111/cge.12932
2016
On the development of extragonadal and gonadal human germ cells
Biol Open. 2016 Feb 1;5(2):185-94. doi: 10.1242/bio.013847.
Heeren AM1, He N1, de Souza AF2, Goercharn-Ramlal A1, van Iperen L1, Roost MS1, Gomes Fernandes MM1, van der Westerlaken LA3, Chuva de Sousa Lopes SM4.
Abstract
Human germ cells originate in an extragonadal location and have to migrate to colonize the gonadal primordia at around seven weeks of gestation (W7, or five weeks post conception). Many germ cells are lost along the way and should enter apoptosis, but some escape and can give rise to extragonadal germ cell tumors. Due to the common somatic origin of gonads and adrenal cortex, we investigated whether ectopic germ cells were present in the human adrenals. Germ cells expressing DDX4 and/or POU5F1 were present in male and female human adrenals in the first and second trimester. However, in contrast to what has been described in mice, where 'adrenal' and 'ovarian' germ cells seem to enter meiosis in synchrony, we were unable to observe meiotic entry in human 'adrenal' germ cells until W22. By contrast, 'ovarian' germ cells at W22 showed a pronounced asynchronous meiotic entry. Interestingly, we observed that immature POU5F1+ germ cells in both first and second trimester ovaries still expressed the neural crest marker TUBB3, reminiscent of their migratory phase. Our findings highlight species-specific differences in early gametogenesis between mice and humans. We report the presence of a population of ectopic germ cells in the human adrenals during development. © 2016. Published by The Company of Biologists Ltd. KEYWORDS: Adrenals; Development; Ectopic; Fetal; Germ cells; Human; Meiosis; Ovaries
PMID 26834021
http://bio.biologists.org/content/5/2/185.long
2013
Fine time course expression analysis identifies cascades of activation and repression and maps a putative regulator of mammalian sex determination
PLoS Genet. 2013 Jul;9(7):e1003630. doi: 10.1371/journal.pgen.1003630. Epub 2013 Jul 11.
Munger SC, Natarajan A, Looger LL, Ohler U, Capel B. Source Department of Cell Biology, Duke University, Durham, North Carolina, USA.
Abstract
In vertebrates, primary sex determination refers to the decision within a bipotential organ precursor to differentiate as a testis or ovary. Bifurcation of organ fate begins between embryonic day (E) 11.0-E12.0 in mice and likely involves a dynamic transcription network that is poorly understood. To elucidate the first steps of sexual fate specification, we profiled the XX and XY gonad transcriptomes at fine granularity during this period and resolved cascades of gene activation and repression. C57BL/6J (B6) XY gonads showed a consistent ~5-hour delay in the activation of most male pathway genes and repression of female pathway genes relative to 129S1/SvImJ, which likely explains the sensitivity of the B6 strain to male-to-female sex reversal. Using this fine time course data, we predicted novel regulatory genes underlying expression QTLs (eQTLs) mapped in a previous study. To test predictions, we developed an in vitro gonad primary cell assay and optimized a lentivirus-based shRNA delivery method to silence candidate genes and quantify effects on putative targets. We provide strong evidence that Lmo4 (Lim-domain only 4) is a novel regulator of sex determination upstream of SF1 (Nr5a1), Sox9, Fgf9, and Col9a3. This approach can be readily applied to identify regulatory interactions in other systems.
PMID 23874228
2012
Mammalian sex determination—insights from humans and mice
Chromosome Res. 2012 Jan;20(1):215-38. doi: 10.1007/s10577-012-9274-3.
Eggers S, Sinclair A. Source Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
Abstract
Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.
PMID 22290220
springeropen
Sex determination strategies in 2012: towards a common regulatory model?
Reprod Biol Endocrinol. 2012 Feb 22;10:13.
Angelopoulou R, Lavranos G, Manolakou P. Source Experimental Embryology Unit, Department of Histology and Embryology, Medical School, Athens University, Athens, Greece. rangelop@med.uoa.gr
Abstract
Sex determination is a complicated process involving large-scale modifications in gene expression affecting virtually every tissue in the body. Although the evolutionary origin of sex remains controversial, there is little doubt that it has developed as a process of optimizing metabolic control, as well as developmental and reproductive functions within a given setting of limited resources and environmental pressure. Evidence from various model organisms supports the view that sex determination may occur as a result of direct environmental induction or genetic regulation. The first process has been well documented in reptiles and fish, while the second is the classic case for avian species and mammals. Both of the latter have developed a variety of sex-specific/sex-related genes, which ultimately form a complete chromosome pair (sex chromosomes/gonosomes). Interestingly, combinations of environmental and genetic mechanisms have been described among different classes of animals, thus rendering the possibility of a unidirectional continuous evolutionary process from the one type of mechanism to the other unlikely. On the other hand, common elements appear throughout the animal kingdom, with regard to a) conserved key genes and b) a central role of sex steroid control as a prerequisite for ultimately normal sex differentiation. Studies in invertebrates also indicate a role of epigenetic chromatin modification, particularly with regard to alternative splicing options. This review summarizes current evidence from research in this hot field and signifies the need for further study of both normal hormonal regulators of sexual phenotype and patterns of environmental disruption. © 2012 Angelopoulou et al; licensee BioMed Central Ltd.
PMID 22357269
Table 1 - Regulatory elements in sex determination/dosage compensation
2009Development of the human Müllerian duct in the sexually undifferentiated stageAn embryological explanation for the development of the Müllerian duct still poses a major challenge. The development of this duct was investigated systematically in human embryos. Seven embryos (Carnegie stages 18-23) were serially sectioned in the frontal, sagittal, and transversal planes at a thickness of 10 microm and stained with hematoxylin and eosin (H&E) for histological analysis. In all observed embryos, the caudal end of the Müllerian duct was found to be intimately connected to the Wolffian duct. The opening of the Müllerian duct to the coelomic cavity was formed as the result of an invagination of the coelomic epithelium at Carnegie stage 18. The duct grew independently from the invagination during stages 19-23. The fused duct (uterovaginal canal) bifurcated at the caudal portion at Carnegie stages 22 and 23. This is the first description of the caudal portion of the fused Müllerian ducts separating again and returning to each of the Wolffian ducts in human embryos. Copyright 2003 Wiley-Liss, Inc. PMID: 12740945
MicroRNA in the ovary and female reproductive tractCarletti MZ, Christenson LK. J Anim Sci. 2009 Apr;87(14 Suppl):E29-38. Epub 2008 Sep 12. Review. PMID: 18791135
Meeting report: measuring endocrine-sensitive endpoints within the first years of life. Arbuckle TE, Hauser R, Swan SH, Mao CS, Longnecker MP, Main KM, Whyatt RM, Mendola P, Legrand M, Rovet J, Till C, Wade M, Jarrell J, Matthews S, Van Vliet G, Bornehag CG, Mieusset R. Environ Health Perspect. 2008 Jul;116(7):948-51. PMID: 18629319 | PMC: 2453165] | Supplementary PDF
Anogenital distance from birth to 2 years: a population studyEnviron Health Perspect. 2009 Nov;117(11):1786-90. Epub 2009 Jul 13. Thankamony A, Ong KK, Dunger DB, Acerini CL, Hughes IA. Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom. Abstract BACKGROUND: Anogenital distance (AGD) is sexually dimorphic in rodents and humans, being 2- to 2.5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. OBJECTIVE: This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. MATERIALS AND METHODS: Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. RESULTS: Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (+/- SD) at birth was 19.8 +/- 6.1 mm in males and 9.1 +/- 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex-dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r = 0.20, p = 0.001). CONCLUSION: We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development. PMID: 20049133 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801188/?tool=pubmed |
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