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Male Sexual Differentiation

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Endocrinology of the Testis and Male Reproduction

Part of the book series: Endocrinology ((ENDOCR))

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Abstract

In mammals, the bipotential genital ridges develop into the testes or ovaries depending on the presence or absence of the Y chromosome. The genital ridges contain three main types of bipotential precursor cells: supporting cells, which in the developing testis differentiate into Sertoli cells, steroidogenic cells giving rise to Leydig cells, and primordial germ cells developing into sperm. Each of these cell types play a critical role in the development and function of adult testes. Expression of the sex-determining region Y gene (Sry) in the supporting cells of the undifferentiated genital ridges initiates a molecular cascade leading to testis differentiation. During this process, carefully orchestrated genetic and physical interactions within and among the cell types residing in the developing testis lead to compartmentalization into two distinct regions, the testis cords and the interstitial space, and ultimately to the full development of the testis. Intriguingly, once determined, gonadal sex and therefore the male or female phenotype must be maintained through active repression of the molecular pathways determining the opposite sex. In this chapter, we will discuss the genetic and cellular mechanisms driving the development of a testis as well as the molecular pathways involved in maintaining gonadal sex.

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References

  • Albrecht KH, Eicher EM. Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor. Dev Biol. 2001;240:92–107.

    Article  CAS  PubMed  Google Scholar 

  • Anderson R, Fässler R, Georges-Labouesse E, et al. Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads. Development. 1999;126:1655–64.

    CAS  PubMed  Google Scholar 

  • Ara T, Nakamura Y, Egawa T, et al. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Proc Natl Acad Sci U S A. 2003;100:5319–23. doi:10.1073/pnas.0730719100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Archambeault DR, Yao HH. Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc Natl Acad Sci U S A. 2010;107:10526–31. doi:10.1073/pnas.1000318107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Auguste A, Chassot A-A, Grégoire EP, et al. Loss of R-spondin1 and Foxl2 amplifies female-to-male sex reversal in XX mice. Sex Dev. 2011;5:304–17. doi:10.1159/000334517.

    Article  CAS  PubMed  Google Scholar 

  • Bagheri-Fam S, Sim H, Bernard P, Jayakody I, Taketo MM, Scherer G, Harley VR. Loss of Fgfr2 leads to partial XY sex reversal. Dev Biol. 2008;314:71–83. doi:10.1016/j.ydbio.2007.11.010.

    Google Scholar 

  • Barbaux S, Niaudet P, Gubler MC, et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 1997;17:467–70. doi:10.1038/ng1297-467.

    Article  CAS  PubMed  Google Scholar 

  • Barrionuevo F, Bagheri-Fam S, Klattig J, et al. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol Reprod. 2006;74:195–201. doi:10.1095/biolreprod.105.045930.

    Article  CAS  PubMed  Google Scholar 

  • Barrionuevo F, Georg I, Scherthan H, et al. Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8. Dev Biol. 2009;327:301–12. doi:10.1016/j.ydbio.2008.12.011 S0012-1606(08)01414-0 [pii].

    Google Scholar 

  • Barrionuevo FJ, Hurtado A, Kim G-J, et al. Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration. Elife. 2016. doi:10.7554/eLife.15635.

    PubMed  PubMed Central  Google Scholar 

  • Barsoum IB, Bingham NC, Parker KL, et al. Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol. 2009;329:96–103. doi:10.1016/j.ydbio.2009.02.025 S0012-1606(09)00155-9 [pii].

    Google Scholar 

  • Baxter RM, Vilain E. Translational genetics for diagnosis of human disorders of sex development. Annu Rev Genomics Hum Genet. 2013;14:371–92. doi:10.1146/annurev-genom-091212-153417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bendel-Stenzel MR, Gomperts M, Anderson R, et al. The role of cadherins during primordial germ cell migration and early gonad formation in the mouse. Mech Dev. 2000;91:143–52.

    Article  CAS  PubMed  Google Scholar 

  • Bendsen E, Byskov AG, Laursen SB, et al. (2003) Number of germ cells and somatic cells in human fetal testes during the first weeks after sex differentiation. Hum Reprod 18:13–8.

    Google Scholar 

  • Bishop CE, Whitworth DJ, Qin Y, et al. A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse. Nat Genet. 2000;26:490–4.

    Article  CAS  PubMed  Google Scholar 

  • Boulanger L, Pannetier M, Gall L, et al. FOXL2 is a female sex-determining gene in the goat. Curr Biol. 2014;24:404–8.

    Article  CAS  PubMed  Google Scholar 

  • Bowles J, Knight D, Smith C, et al. Retinoid signaling determines germ cell fate in mice. Science (80- ). 2006;312:596–600.

    Article  CAS  Google Scholar 

  • Brennan J, Karl J, Capel B. Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad. Dev Biol. 2002;244:418–28.

    Article  CAS  PubMed  Google Scholar 

  • Brennan J, Tilmann C, Capel B. Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev. 2003;17:800–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Britt KL, Drummond AE, Dyson M, et al. The ovarian phenotype of the aromatase knockout (ArKO) mouse. J Steroid Biochem Mol Biol. 2001;79:181–5. doi:10.1016/S0960-0760(01)00158-3.

    Article  CAS  PubMed  Google Scholar 

  • Buehr M, Gu S, McLaren A. Mesonephric contribution to testis differentiation in the fetal mouse. Development. 1993a;117:273–81.

    CAS  PubMed  Google Scholar 

  • Buehr M, McLaren A, Bartley A, Darling S. Proliferation and migration of primordial germ cells in We/We mouse embryos. Dev Dyn. 1993b;198:182–9. doi:10.1002/aja.1001980304.

    Article  CAS  PubMed  Google Scholar 

  • Bullejos M, Koopman P. Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn. 2001;221:201–5.

    Article  CAS  PubMed  Google Scholar 

  • Bullejos M, Koopman P. Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-Y(DOM) sex reversal. Dev Biol. 2005;278:473–81.

    Article  CAS  PubMed  Google Scholar 

  • Callier P, Calvel P, Matevossian A, et al. Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genet. 2014;10:e1004340. doi:10.1371/journal.pgen.1004340.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Canto P, Soderlund D, Reyes E, Mendez JP. Mutations in the desert hedgehog (DHH) gene in patients with 46,XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab. 2004;89:4480–3. doi:10.1210/jc.2004-0863.

    Article  CAS  PubMed  Google Scholar 

  • Chaboissier MC, Kobayashi A, Vidal VI, et al. Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development. 2004;131:1891–901. doi:10.1242/dev.01087.

    Article  CAS  PubMed  Google Scholar 

  • Chassot AA, Ranc F, Gregoire EP, et al. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet. 2008;17:1264–77. doi:10.1093/hmg/ddn016.

    Article  CAS  PubMed  Google Scholar 

  • Childs AJ, Cowan G, Kinnell HL, et al. Retinoic acid signalling and the control of meiotic entry in the human fetal gonad. PLoS One. 2011;6:e20249. doi:10.1371/journal.pone.0020249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clark AM, Garland KK, Russell LD. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Biol Reprod. 2000;63:1825–38.

    Article  CAS  PubMed  Google Scholar 

  • Combes AN, Lesieur E, Harley VR, et al. Three-dimensional visualization of testis cord morphogenesis, a novel tubulogenic mechanism in development. Dev Dyn. 2009a;238:1033–41. doi:10.1002/dvdy.21925.

    Article  PubMed  PubMed Central  Google Scholar 

  • Combes AN, Wilhelm D, Davidson T, et al. Endothelial cell migration directs testis cord formation. Dev Biol. 2009b;326:112–20. doi:10.1016/j.ydbio.2008.10.040.

    Article  CAS  PubMed  Google Scholar 

  • Cool J, Carmona FD, Szucsik JC, Capel B. Peritubular myoid cells are not the migrating population required for testis cord formation in the XY gonad. Sex Dev. 2008;2:128–33. doi:10.1159/000143430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couse JF, Hewitt SC, Bunch DO, et al. Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science. 1999;286:2328–31.

    Article  CAS  PubMed  Google Scholar 

  • Coveney D, Shaw G, Renfree MB. Estrogen-induced gonadal sex reversal in the tammar wallaby. Biol Reprod. 2001;65:613–21.

    Article  CAS  PubMed  Google Scholar 

  • Coveney D, Cool J, Oliver T, Capel B. Four-dimensional analysis of vascularization during primary development of an organ, the gonad. Proc Natl Acad Sci U S A. 2008;105:7212–7. doi:10.1073/pnas.0707674105 0707674105 [pii].

    Google Scholar 

  • Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27:159–66. doi:10.1038/84781.

    Article  CAS  PubMed  Google Scholar 

  • Das DK, Sanghavi D, Gawde H, et al. Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods. Eur J Med Genet. 2011;54:e529–34. doi:10.1016/j.ejmg.2011.04.010.

    Article  PubMed  Google Scholar 

  • De Felici M. Origin, migration, and proliferation of human primordial germ cells. In: Cotichhio G, Albertini DF, Santis L, editors. Oogenesis. London: Springer; 2013. p. 19–37.

    Chapter  Google Scholar 

  • DeFalco T, Takahashi S, Capel B. Two distinct origins for Leydig cell progenitors in the fetal testis. Dev Biol. 2011;352:14–26. doi:10.1016/j.ydbio.2011.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Carlo A, De Felici M. A role for E-cadherin in mouse primordial germ cell development. Dev Biol. 2000;226:209–19. doi:10.1006/dbio.2000.9861S0012-1606(00)99861-0 [pii].

    Google Scholar 

  • Dias V, Meachem S, Rajpert-De Meyts E, et al. Activin receptor subunits in normal and dysfunctional adult human testis. Hum Reprod. 2008;23:412–20. doi:10.1093/humrep/dem343.

    Article  CAS  PubMed  Google Scholar 

  • Dupont S, Krust A, Gansmuller A, et al. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development. 2000;127:4277–91.

    CAS  PubMed  Google Scholar 

  • Dupont S, Dennefeld C, Krust A, et al. Expression of Sox9 in granulosa cells lacking the estrogen receptors, ERalpha and ERbeta. Dev Dyn. 2003;226:103–6.

    Article  CAS  PubMed  Google Scholar 

  • Eggers S, Sinclair A. Mammalian sex determination-insights from humans and mice. Chromosom Res. 2012;20:215–38. doi:10.1007/s10577-012-9274-3.

    Article  CAS  Google Scholar 

  • Ewen KA, Koopman P. Mouse germ cell development: from specification to sex determination. Mol Cell Endocrinol. 2010;323:76–93. doi:10.1016/j.mce.2009.12.013.

    Article  CAS  PubMed  Google Scholar 

  • Fahrioglu U, Murphy MW, Zarkower D, Bardwell VJ. mRNA expression analysis and the molecular basis of neonatal testis defects in Dmrt1 mutant mice. Sex Dev. 2007;1:42–58. doi:10.1159/000096238.

    Article  CAS  PubMed  Google Scholar 

  • Fitzpatrick SL, Funkhouser JM, Sindoni DM, et al. Expression of estrogen receptor-beta protein in rodent ovary. Endocrinology. 1999;140:2581–91. doi:10.1210/endo.140.6.6928.

    Article  CAS  PubMed  Google Scholar 

  • Foster JW, Dominguez-Steglich MA, Guioli S, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;372:525–30.

    Article  CAS  PubMed  Google Scholar 

  • França LR, Hess RA, Dufour JM, et al. The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology. 2016;4:189–212. doi:10.1111/andr.12165.

    Article  PubMed  CAS  Google Scholar 

  • Gao F, Maiti S, Alam N, et al. The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis. Proc Natl Acad Sci U S A. 2006;103:11987–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • García-Castro MI, Anderson R, Heasman J, Wylie C. Interactions between germ cells and extracellular matrix glycoproteins during migration and gonad assembly in the mouse embryo. J Cell Biol. 1997;138:471–80.

    Article  PubMed  PubMed Central  Google Scholar 

  • Garcia-Ortiz JE, Pelosi E, Omari S, et al. Foxl2 functions in sex determination and histogenesis throughout mouse ovary development. BMC Dev Biol. 2009;9:36. doi:10.1186/1471-213X-9-36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Georg I, Barrionuevo F, Wiech T, Scherer G. Sox9 and Sox8 are required for basal lamina integrity of testis cords and for suppression of FOXL2 during embryonic testis development in mice. Biol Reprod. 2012;87:99. doi:10.1095/biolreprod.112.101907.

    Article  PubMed  CAS  Google Scholar 

  • Georges A, L’Hôte D, Todeschini AL, et al. The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells. Elife. 2014. doi:10.7554/eLife.04207.

    PubMed  PubMed Central  Google Scholar 

  • Ghyselinck NB, Vernet N, Dennefeld C, et al. Retinoids and spermatogenesis: lessons from mutant mice lacking the plasma retinol binding protein. Dev Dyn. 2006;235:1608–22. doi:10.1002/dvdy.20795.

    Article  CAS  PubMed  Google Scholar 

  • Godin I, Wylie CC. TGFbeta inhibits proliferation and has a chemotrophic effect on mouse primoridal germ cells in culture. Development. 1991;113:1451–7.

    CAS  PubMed  Google Scholar 

  • Griswold MD. Interactions between germ cells and Sertoli cells in the testis. Biol Reprod. 1995;52:211–6.

    Article  CAS  PubMed  Google Scholar 

  • Hadley MA, Byers SW, Suárez-Quian CA, et al. Extracellular matrix regulates Sertoli cell differentiation, testicular cord formation, and germ cell development in vitro. J Cell Biol. 1985;101:1511–22.

    Article  CAS  PubMed  Google Scholar 

  • Hanley NA, Hagan DM, Clement-Jones M, Ball SG, Strachan T, Salas-Cortés L, McElreavey K, Lindsay S, Robson S, Bullen P, Ostrer H, Wilson DI. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev. 2000; 91:403–7. doi: 10.1016/S0925-4773(99)00307-X.

    Google Scholar 

  • Hasegawa K, Saga Y. Retinoic acid signaling in Sertoli cells regulates organization of the blood-testis barrier through cyclical changes in gene expression. Development. 2012;139:4347–55. doi:10.1242/dev.080119.

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto N, Kubokawa R, Yamazaki K, et al. Germ cell deficiency causes testis cord differentiation in reconstituted mouse fetal ovaries. J Exp Zool. 1990;253:61–70. doi:10.1002/jez.1402530109.

    Article  CAS  PubMed  Google Scholar 

  • Hillier SG, Whitelaw PF, Smyth CD. Follicular oestrogen synthesis: the “two-cell, two-gonadotrophin” model revisited. Mol Cell Endocrinol. 1994;100:51–4.

    Article  CAS  PubMed  Google Scholar 

  • Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. J Pediatr Urol. 2006;2:148–62. doi:10.1016/j.jpurol.2006.03.004.

    Article  CAS  PubMed  Google Scholar 

  • Irie N, Weinberger L, Tang WWC, et al. SOX17 is a critical specifier of human primordial germ cell fate. Cell. 2015;160:253–68. doi:10.1016/j.cell.2014.12.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jadresic L, Leake J, Gordon I, et al. Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome). J Pediatr. 1990;117:717–25.

    Article  CAS  PubMed  Google Scholar 

  • Karl J, Capel B. Sertoli cells of the mouse testis originate from the coelomic epithelium. Dev Biol. 1998;203:323–33.

    Article  CAS  PubMed  Google Scholar 

  • Kashimada K, Svingen T, Feng CW, et al. Antagonistic regulation of Cyp26b1 by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice. FASEB J. 2011;25:3561–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kato T, Miyata K, Sonobe M, et al. Production of Sry knockout mouse using TALEN via oocyte injection. Sci Rep. 2013;3:3136. doi:10.1038/srep03136.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim Y, Kobayashi A, Sekido R, et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. 2006;4:e187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim Y, Bingham N, Sekido R, Parker KL, Lovell-Badge R, Capel B. Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination. Proc Natl Acad Sci U S A. 2007;104:16558–63. doi:10.1073/pnas.0702581104.

    Google Scholar 

  • Kim S, Bardwell VJ, Zarkower D. Cell type-autonomous and non-autonomous requirements for Dmrt1 in postnatal testis differentiation. Dev Biol. 2007;307:314–27. doi:10.1016/j.ydbio.2007.04.046 S0012-1606(07)00869-X [pii].

    Google Scholar 

  • Kitamura K, Yanazawa M, Sugiyama N, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet. 2002; 32:359–69. doi:10.1038/ng1009 ng1009 [pii].

    Google Scholar 

  • Koopman P, Gubbay J, Vivian N, et al. Male development of chromosomally female mice transgenic for Sry. Nature. 1991;351:117–21.

    Article  CAS  PubMed  Google Scholar 

  • Koubova J, Menke DB, Zhou Q, et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A. 2006;103:2474–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurimoto K, Yabuta Y, Ohinata Y, et al. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev. 2008;22:1617–35. doi:10.1101/gad.1649908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lambeth LS, Raymond CS, Roeszler KN, et al. Over-expression of DMRT1 induces the male pathway in embryonic chicken gonads. Dev Biol. 2014;389:160–72. doi:10.1016/j.ydbio.2014.02.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavery R, Chassot AA, Pauper E, et al. Testicular differentiation occurs in absence of R-spondin1 and Sox9 in mouse sex reversals. PLoS Genet. 2012;8:e1003170. doi:10.1371/journal.pgen.1003170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee D-G, Han DH, Park KH, Baek M. A novel WT1 gene mutation in a patient with Wilms’ tumor and 46, XY gonadal dysgenesis. Eur J Pediatr. 2011;170:1079–82. doi:10.1007/s00431-011-1439-0.

    Article  PubMed  Google Scholar 

  • Lei N, Hornbaker KI, Rice DA, et al. Sex-specific differences in mouse DMRT1 expression are both cell type- and stage-dependent during gonad development. Biol Reprod. 2007;77:466–75. doi:10.1095/biolreprod.106.058784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindeman RE, Gearhart MD, Minkina A, et al. Sexual cell-fate reprogramming in the ovary by DMRT1. Curr Biol. 2015;25:764–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacLean G, Li H, Metzger D, et al. Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology. 2007;148:4560–7. doi:10.1210/en.2007-0492.

    Article  CAS  PubMed  Google Scholar 

  • Maekawa M, Kamimura K, Nagano T. Peritubular myoid cells in the testis: their structure and function. Arch Histol Cytol. 1996;59:1–13.

    Article  CAS  PubMed  Google Scholar 

  • Mahakali Zama A, Hudson FP, Bedell MA. Analysis of hypomorphic KitlSl mutants suggests different requirements for KITL in proliferation and migration of mouse primordial germ cells. Biol Reprod. 2005;73:639–47. doi:10.1095/biolreprod.105.042846.

    Article  PubMed  CAS  Google Scholar 

  • Majdic G, McNeilly AS, Sharpe RM, et al. Testicular expression of inhibin and activin subunits and follistatin in the rat and human fetus and neonate and during postnatal development in the rat. Endocrinology. 1997;138:2136–47. doi:10.1210/endo.138.5.5135.

    Article  CAS  PubMed  Google Scholar 

  • Malki S, Nef S, Notarnicola C, et al. Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. EMBO J. 2005;24:1798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mamsen LS, Lutterodt MC, Andersen EW, et al. Germ cell numbers in human embryonic and fetal gonads during the first two trimesters of pregnancy: analysis of six published studies. Hum Reprod. 2011;26:2140–5. doi:10.1093/humrep/der149.

    Article  PubMed  Google Scholar 

  • Martineau J, Nordqvist K, Tilmann C, et al. Male-specific cell migration into the developing gonad. Curr Biol. 1997;7:958–68.

    Article  CAS  PubMed  Google Scholar 

  • Matoba S, Kanai Y, Kidokoro T, et al. A novel Sry-downstream cellular event which preserves the readily available energy source of glycogen in mouse sex differentiation. J Cell Sci. 2005;118:1449–59. doi:10.1242/jcs.01738.

    Article  CAS  PubMed  Google Scholar 

  • Matoba S, Hiramatsu R, Kanai-Azuma M, et al. Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation. Dev Biol. 2008;324:76–87. doi:10.1016/j.ydbio.2008.09.004.

    Article  CAS  PubMed  Google Scholar 

  • Matson CK, Murphy MW, Sarver AL, et al. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature. 2011;476:101–4. doi:10.1038/nature10239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda M, Nagahama Y, Shinomiya A, et al. DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature. 2002;417:559–63.

    Article  CAS  PubMed  Google Scholar 

  • Matsuda M, Shinomiya A, Kinoshita M, et al. DMY gene induces male development in genetically female (XX) medaka fish. Proc Natl Acad Sci U S A. 2007;104:3865–70. doi:10.1073/pnas.0611707104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCoshen JA, McCallion DJ. A study of the primordial germ cells during their migratory phase in Steel mutant mice. Experientia. 1975;31:589–90.

    Article  CAS  PubMed  Google Scholar 

  • McLaren A. Primordial germ cells in the mouse. Dev Biol. 2003;262:1–15.

    Article  CAS  PubMed  Google Scholar 

  • Mendis SH, Meachem SJ, Sarraj MA, Loveland KL. Activin A balances Sertoli and germ cell proliferation in the fetal mouse testis. Biol Reprod. 2011;84:379–91. doi:10.1095/biolreprod.110.086231.

    Article  CAS  PubMed  Google Scholar 

  • Merchant-Larios H, Moreno-Mendoza N. Mesonephric stromal cells differentiate into Leydig cells in the mouse fetal testis. Exp Cell Res. 1998;244:230–8. doi:10.1006/excr.1998.4215. S0014-4827(98)94215-X [pii].

    Google Scholar 

  • Merchant-Larios H, Moreno-Mendoza N, Buehr M. The role of the mesonephros in cell differentiation and morphogenesis of the mouse fetal testis. Int J Dev Biol. 1993;37:407–15.

    CAS  PubMed  Google Scholar 

  • Miles DC, Wakeling SI, Stringer JM, et al. Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PLoS One. 2013;8:e54606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minkina A, Matson CK, Lindeman RE, et al. DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev Cell. 2014;29:511–20. doi:10.1016/j.devcel.2014.04.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mintz B, Russell ES. Gene-induced embryological modifications of primordial germ cells in the mouse. J Exp Zool. 1957;134:207–37.

    Article  CAS  PubMed  Google Scholar 

  • Miyabayashi K, Katoh-Fukui Y, Ogawa H, et al. Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells. PLoS One. 2013;8:e68050. doi:10.1371/journal.pone.0068050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molyneaux KA, Stallock J, Schaible K, Wylie C. Time-lapse analysis of living mouse germ cell migration. Dev Biol. 2001;240:488–98. doi:10.1006/dbio.2001.0436.

    Article  CAS  PubMed  Google Scholar 

  • Molyneaux KA, Zinszner H, Kunwar PS, et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development. 2003;130:4279–86.

    Article  CAS  PubMed  Google Scholar 

  • Moniot B, Berta P, Scherer G, et al. Male specific expression suggests role of DMRT1 in human sex determination. Mech Dev. 2000;91:323–5.

    Article  CAS  PubMed  Google Scholar 

  • Moniot B, Declosmenil F, Barrionuevo F, et al. The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation. Development. 2009;136:1813–21. doi:10.1242/dev.032631 136/11/1813 [pii].

    Google Scholar 

  • Moreno SG, Attali M, Allemand I, et al. TGFbeta signaling in male germ cells regulates gonocyte quiescence and fertility in mice. Dev Biol. 2010;342:74–84. doi:10.1016/j.ydbio.2010.03.007.

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Mendoza N, Herrera-Muñoz J, Merchant-Larios H. Limb bud mesenchyme permits seminiferous cord formation in the mouse fetal testis but subsequent testosterone output is markedly affected by the sex of the donor stromal tissue. Dev Biol. 1995;169:51–6. doi:10.1006/dbio.1995.1125.

    Article  CAS  PubMed  Google Scholar 

  • Murphy MW, Sarver AL, Rice D, et al. Genome-wide analysis of DNA binding and transcriptional regulation by the mammalian Doublesex homolog DMRT1 in the juvenile testis. Proc Natl Acad Sci U S A. 2010;107:13360–5. doi:10.1073/pnas.1006243107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nanda I, Kondo M, Hornung U, et al. A duplicated copy of DMRT1 in the sex-determining region of the Y chromosome of the medaka, Oryzias latipes. Proc Natl Acad Sci U S A. 2002;99:11778–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nel-Themaat L, Vadakkan TJ, Wang Y, et al. Morphometric analysis of testis cord formation in Sox9-EGFP mice. Dev Dyn. 2009;238:1100–10. doi:10.1002/dvdy.21954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nel-Themaat L, Jang C-W, Stewart MD, et al. Sertoli cell behaviors in developing testis cords and postnatal seminiferous tubules of the mouse. Biol Reprod. 2011;84:342–50. doi:10.1095/biolreprod.110.086900.

    Article  CAS  PubMed  Google Scholar 

  • Nicholls PK, Harrison CA, Rainczuk KE, et al. Retinoic acid promotes Sertoli cell differentiation and antagonises activin-induced proliferation. Mol Cell Endocrinol. 2013;377:33–43. doi:10.1016/j.mce.2013.06.034.

    Article  CAS  PubMed  Google Scholar 

  • Nishino K, Yamanouchi K, Naito K, Tojo H. Characterization of mesonephric cells that migrate into the XY gonad during testis differentiation. Exp Cell Res. 2001;267:225–32. doi:10.1006/excr.2001.5238S0014-4827(01)95238-3 [pii].

    Google Scholar 

  • O’Shaughnessy PJ, Baker PJ, Heikkilä M, et al. Localization of 17beta-hydroxysteroid dehydrogenase/17-ketosteroid reductase isoform expression in the developing mouse testis – androstenedione is the major androgen secreted by fetal/neonatal leydig cells. Endocrinology. 2000;141:2631–7. doi:10.1210/endo.141.7.7545.

    Article  Google Scholar 

  • O’Shaughnessy PJ, Baker PJ, Johnston H. The foetal Leydig cell– differentiation, function and regulation. Int J Androl. 2006;29:90–5. doi:10.1111/j.1365-2605.2005.00555.x. discussion 105–8.

    Article  PubMed  CAS  Google Scholar 

  • O’Shaughnessy PJ, Baker PJ, Monteiro A, et al. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J Clin Endocrinol Metab. 2007;92:4792–801. doi:10.1210/jc.2007-1690.

    Article  PubMed  CAS  Google Scholar 

  • Ogata T, Matsuo N, Hiraoka N, Hata JI. X-linked lissencephaly with ambiguous genitalia: delineation of further case. Am J Med Genet. 2000;94:174–6.

    Article  CAS  PubMed  Google Scholar 

  • Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013;9:79–91. doi:10.1038/nrendo.2012.235.

    Article  CAS  PubMed  Google Scholar 

  • Ostrer H. Disorders of sex development (DSDs): an update. J Clin Endocrinol Metab. 2014;99:1503–9. doi:10.1210/jc.2013-3690.

    Article  CAS  PubMed  Google Scholar 

  • Otake H, Masuyama H, Mashima Y, et al. Heritable artificial sex chromosomes in the medaka, Oryzias latipes. Heredity (Edinb). 2010;105:247–56. doi:10.1038/hdy.2009.174.

    Article  CAS  Google Scholar 

  • Ottolenghi C, Omari S, Garcia-Ortiz JE, et al. Foxl2 is required for commitment to ovary differentiation. Hum Mol Genet. 2005;14:2053–62. doi:10.1093/hmg/ddi210.

    Article  CAS  PubMed  Google Scholar 

  • Ottolenghi C, Pelosi E, Tran J, et al. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet. 2007;16:2795–804. doi:10.1093/hmg/ddm235 ddm235 [pii].

    Google Scholar 

  • Pailhoux E, Vigier B, Chaffaux S, et al. A 11.7-kb deletion triggers intersexuality and polledness in goats. Nat Genet. 2001;29:453–8. doi:10.1038/ng769.

    Article  CAS  PubMed  Google Scholar 

  • Park SY, Tong M, Jameson JL. Distinct roles for steroidogenic factor 1 and desert hedgehog pathways in fetal and adult Leydig cell development. Endocrinology. 2007;148:3704–10. doi:10.1210/en.2006-1731.

    Article  CAS  PubMed  Google Scholar 

  • Pask AJ, Calatayud NE, Shaw G, et al. Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal. BMC Biol. 2010;8:113. doi:10.1186/1741-7007-8-113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pelletier J, Bruening W, Kashtan CE, et al. Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991;67:437–47.

    Article  CAS  PubMed  Google Scholar 

  • Pierucci-Alves F, Clark AM, Russell LD. A developmental study of the Desert hedgehog-null mouse testis. Biol Reprod. 2001;65:1392–402.

    Article  CAS  PubMed  Google Scholar 

  • Raverdeau M, Gely-Pernot A, Feret B, et al. Retinoic acid induces Sertoli cell paracrine signals for spermatogonia differentiation but cell autonomously drives spermatocyte meiosis. Proc Natl Acad Sci. 2012;109:16582–7. doi:10.1073/pnas.1214936109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raymond CS, Shamu CE, Shen MM, et al. Evidence for evolutionary conservation of sex-determining genes. Nature. 1998;391:691–5.

    Article  CAS  PubMed  Google Scholar 

  • Raymond CS, Kettlewell JR, Hirsch B, et al. Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development. Dev Biol. 1999;215:208–20. doi:10.1006/dbio.1999.9461.

    Article  CAS  PubMed  Google Scholar 

  • Raymond CS, Murphy MW, O’Sullivan MG, et al. Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 2000;14:2587–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richards AJ, Enders GC, Resnick JL. Activin and TGFbeta limit murine primordial germ cell proliferation. Dev Biol. 1999;207:470–5. doi:10.1006/dbio.1998.9174.

    Article  CAS  PubMed  Google Scholar 

  • Rios-Rojas C, Spiller C, Bowles J, Koopman P. Germ cells influence cord formation and leydig cell gene expression during mouse testis development. Dev Dyn. 2016;245:433–44. doi:10.1002/dvdy.24371.

    Article  CAS  PubMed  Google Scholar 

  • Runyan C, Schaible K, Molyneaux K, et al. Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development. 2006;133:4861–9. doi:10.1242/dev.02688.

    Article  CAS  PubMed  Google Scholar 

  • Saitou M. Specification of the germ cell lineage in mice. Front Biosci (Landmark Ed). 2009;14:1068–87.

    Article  CAS  Google Scholar 

  • Saitou M. Germ cell specification in mice. Curr Opin Genet Dev. 2009;19:386–95. doi:10.1016/j.gde.2009.06.003.

    Article  CAS  PubMed  Google Scholar 

  • Saitou M, Yamaji M. Germ cell specification in mice: signaling, transcription regulation, and epigenetic consequences. Reproduction. 2010;139:931–42. doi:10.1530/REP-10-0043.

    Article  CAS  PubMed  Google Scholar 

  • Saitou M, Payer B, O’Carroll D, et al. Blimp1 and the emergence of the germ line during development in the mouse. Cell Cycle. 2005;4:1736–40. doi:10.4161/cc.4.12.2209.

    Article  CAS  PubMed  Google Scholar 

  • Sar M, Welsch F. Differential expression of estrogen receptor-beta and estrogen receptor-alpha in the rat ovary. Endocrinology. 1999;140:963–71. doi:10.1210/endo.140.2.6533.

    Article  CAS  Google Scholar 

  • Schmahl J, Capel B. Cell proliferation is necessary for the determination of male fate in the gonad. Dev Biol. 2003;258:264–76. doi:10.1016/S0012-1606(03)00122-2.

    Article  CAS  PubMed  Google Scholar 

  • Schmahl J, Eicher E, Washburn L, Capel B. Sry induces cell proliferation in the mouse gonad. Development. 2000;127:65–73.

    CAS  PubMed  Google Scholar 

  • Schmidt D, Ovitt CE, Anlag K, et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004;131:933–42.

    Article  CAS  PubMed  Google Scholar 

  • Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature. 2008;453:930–4.

    Article  CAS  PubMed  Google Scholar 

  • Sertoli E. Dell’esistenza di particolari cellule ramificate nei canalicoli seminiferi del testicolo umano. Morgagni. 1865;7:31–40.

    Google Scholar 

  • Shima Y, Miyabayashi K, Haraguchi S, et al. Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testes. Mol Endocrinol. 2013;27:63–73. doi:10.1210/me.2012-1256.

    Article  CAS  PubMed  Google Scholar 

  • Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4.

    Article  CAS  PubMed  Google Scholar 

  • Skinner MK. Secretion of growth factors and other regulatory factors. In: Russell LD, Griswold MD, editors. The Sertoli cell. Clearwater: Cache River Press; 1993. p. 237–47.

    Google Scholar 

  • Smith CA, McClive PJ, Hudson Q, Sinclair AH. Male-specific cell migration into the developing gonad is a conserved process involving PDGF signalling. Dev Biol. 2005;284:337–50.

    Article  CAS  PubMed  Google Scholar 

  • Smith CA, Roeszler KN, Ohnesorg T, et al. The avian Z-linked gene DMRT1 is required for male sex determination in the chicken. Nature. 2009;461:267–71. doi:10.1038/nature08298 nature08298 [pii].

    Google Scholar 

  • Spiller C, Wilhelm D, Koopman P. Cell cycle analysis of fetal germ cells during sex differentiation in mice. Biol Cell. 2009;101:587–98. doi:10.1042/BC20090021.

    Article  PubMed  PubMed Central  Google Scholar 

  • Spiller CM, Wilhelm D, Koopman P. Retinoblastoma 1 protein modulates XY germ cell entry into G1/G0 arrest during fetal development in mice. Biol Reprod. 2010;82:433–43. doi:10.1095/biolreprod.109.078691.

    Article  CAS  PubMed  Google Scholar 

  • Tam PP, Snow MH. Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morpholog. 1981;64:133–47.

    CAS  Google Scholar 

  • Tang H, Brennan J, Karl J, et al. Notch signaling maintains Leydig progenitor cells in the mouse testis. Development. 2008;135:3745–53. doi:10.1242/dev.024786 dev.024786 [pii].

    Google Scholar 

  • Tripiciano A, Filippini A, Giustiniani Q, Palombi F. Direct visualization of rat peritubular myoid cell contraction in response to endothelin. Biol Reprod. 1996;55:25–31.

    Article  CAS  PubMed  Google Scholar 

  • Uhlenhaut NH, Jakob S, Anlag K, et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell. 2009;139:1130–42. doi:10.1016/j.cell.2009.11.021 S0092-8674(09)01433-0 [pii].

    Google Scholar 

  • Umehara F, Tate G, Itoh K, et al. A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet. 2000;67:1302–5. doi:10.1016/S0002-9297(07)62958-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vergouwen RP, Jacobs SG, Huiskamp R, et al. Proliferative activity of gonocytes, Sertoli cells and interstitial cells during testicular development in mice. J Reprod Fertil. 1991;93:233–43.

    Article  CAS  PubMed  Google Scholar 

  • Vidal VPI, Chaboissier MC, de Rooij DG, Schedl A. Sox9 induces testis development in XX transgenic mice. Nat Genet. 2001;28:216–7.

    Article  CAS  PubMed  Google Scholar 

  • Wagner T, Wirth J, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79:1111–20.

    Article  CAS  PubMed  Google Scholar 

  • Wen Q, Liu Y, Gao F. Fate determination of fetal Leydig cells. Front Biol (Beijing). 2011;6:12–8. doi:10.1007/s11515-011-1100-3.

    Article  Google Scholar 

  • Wen Q, Zheng Q-S, Li X-X, et al. Wt1 dictates the fate of fetal and adult Leydig cells during development in the mouse testis. Am J Physiol Endocrinol Metab. 2014;307:E1131–43. doi:10.1152/ajpendo.00425.2014.

    Article  CAS  PubMed  Google Scholar 

  • Western PS, Miles DC, van den Bergen JA, et al. Dynamic regulation of mitotic arrest in fetal male germ cells. Stem Cells. 2008;26:339–47. doi:10.1634/stemcells.2007-0622.

    Article  CAS  PubMed  Google Scholar 

  • Wilhelm D, Martinson F, Bradford S, et al. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev Biol. 2005;287:111–24. doi:10.1016/j.ydbio.2005.08.039.

    Article  CAS  PubMed  Google Scholar 

  • Wilhelm D, Hiramatsu R, Mizusaki H, et al. SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J Biol Chem. 2007;282:10553–60.

    Article  CAS  PubMed  Google Scholar 

  • Yamaji M, Seki Y, Kurimoto K, et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet. 2008;40:1016–22. doi:10.1038/ng.186.

    Article  CAS  PubMed  Google Scholar 

  • Yao HH-C, Capel B. Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev Biol. 2002;246:356–65. doi:10.1006/dbio.2002.0663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao HH-C, Whoriskey W, Capel B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev. 2002;16:1433–40. doi:10.1101/gad.981202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshimoto S, Ikeda N, Izutsu Y, et al. Opposite roles of DMRT1 and its W-linked paralogue, DM-W, in sexual dimorphism of Xenopus laevis: implications of a ZZ/ZW-type sex-determining system. Development. 2010;137:2519–26. doi:10.1242/dev.048751.

    Article  CAS  PubMed  Google Scholar 

  • Young JM, McNeilly AS. Theca: the forgotten cell of the ovarian follicle. Reproduction. 2010;140:489–504. doi:10.1530/REP-10-0094.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Chen M, Wen Q, et al. Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation. Proc Natl Acad Sci U S A. 2015;112:4003–8. doi:10.1073/pnas.1422371112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao L, Svingen T, Ng ET, Koopman P. Female-to-male sex reversal in mice caused by transgenic overexpression of Dmrt1. Development. 2015;142:1083–8. doi:10.1242/dev.122184.

    Article  CAS  PubMed  Google Scholar 

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Sterling, C.H., Wilhelm, D., Bagheri-Fam, S. (2017). Male Sexual Differentiation. In: Simoni, M., Huhtaniemi, I. (eds) Endocrinology of the Testis and Male Reproduction. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-29456-8_6-1

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