Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Genetic regulation of mammalian gonad development

Key Points

  • The critical testis-determining genes are Sry and Sox9; however, many genes upstream of Sry and downstream of Sry and Sox9 are also important for correct testis development

  • Novel factors have been identified in the known pathways of the testis-determining network, including Six1, Six4, Map3k4, Gadd45g and Hhat

  • Ovarian development lacks a single genetic switch; however, genes such as Rspo1, Foxl2, Wnt4 and Ctnnb1 seem to be essential for correct ovary development

  • Both the testis-determining and ovary-determining pathways have active gene networks that must be maintained throughout life by suppression of the opposing pathway

  • As well as regulation of gene expression by transcription factors, other types of gene control, such as noncoding RNAs and epigenetic modification, are required for gonad development

Abstract

Sex-specific gonadal development starts with formation of the bipotential gonad, which then differentiates into either a mature testis or an ovary. This process is dependent on activation of either the testis-specific or the ovary-specific pathway while the opposite pathway is continuously repressed. A network of transcription factors tightly regulates initiation and maintenance of these distinct pathways; disruption of these networks can lead to disorders of sex development in humans and male-to-female or female-to-male sex reversal in mice. Sry is the Y-linked master switch that is both required and sufficient to drive the testis-determining pathway. Another key component of the testis pathway is Sox9, which acts immediately downstream of Sry. In contrast to the testis pathway, no single sex-determining factor has been identified in the ovary pathway; however, multiple genes, such as Foxl2, Rspo1, Ctnnb1, and Wnt4, seem to work synergistically and in parallel to ensure proper ovary development. Our understanding of the regulatory networks that underpin testis and ovary development has grown substantially over the past two decades.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genes and pathways required for the development of the bipotential gonad.
Figure 2: Genes and pathways required for testis development and differentiation.
Figure 3: Genes and pathways required for ovary development and differentiation.
Figure 4: Interactions between the testis-specific and ovary-specific pathways during embryonic development and adulthood.

Similar content being viewed by others

References

  1. Biason-Lauber, A. Control of sex development. Best Pract. Res. Clin. Endocrinol. Metab. 24, 163–186 (2010).

    PubMed  Google Scholar 

  2. Wainwright, E. N. et al. SOX9 regulates microRNA miR2025p/3p expression during mouse testis differentiation. Biol. Reprod. 89, 34 (2013).

    PubMed  Google Scholar 

  3. Kuroki, S. et al. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 341, 1106–1109 (2013).

    CAS  PubMed  Google Scholar 

  4. Bosze, P., Szabo, D., Laszlo, J. & Gaal, M. Ultrastructure of the fibrous tissue of the streak gonads. Acta Med. Acad. Sci. Hung. 39, 133–135 (1982).

    CAS  PubMed  Google Scholar 

  5. Miyamoto, N., Yoshida, M., Kuratani, S., Matsuo, I. & Aizawa, S. Defects of urogenital development in mice lacking Emx2. Development 124, 1653–1664 (1997).

    CAS  PubMed  Google Scholar 

  6. Birk, O. S. et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature 403, 909–913 (2000).

    CAS  PubMed  Google Scholar 

  7. Wilhelm, D. & Englert, C. The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev. 16, 1839–1851 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Val, P., Lefrancois-Martinez, A. M., Veyssiere, G. & Martinez, A. SF1 a key player in the development and differentiation of steroidogenic tissues. Nucl. Recept. 1, 8 (2003).

    PubMed  PubMed Central  Google Scholar 

  9. Luo, X., Ikeda, Y. & Parker, K. L. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490 (1994).

    CAS  PubMed  Google Scholar 

  10. Sekido, R. & Lovell-Badge, R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453, 930–934 (2008).

    CAS  PubMed  Google Scholar 

  11. Nachtigal, M. W. et al. Wilms' tumor 1 and Dax1 modulate the orphan nuclear receptor SF1 in sex-specific gene expression. Cell 93, 445–454 (1998).

    CAS  PubMed  Google Scholar 

  12. Kreidberg, J. A. et al. WT1 is required for early kidney development. Cell 74, 679–691 (1993).

    CAS  PubMed  Google Scholar 

  13. Hammes, A. et al. Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106, 319–329 (2001).

    CAS  PubMed  Google Scholar 

  14. Katoh-Fukui, Y. et al. Male-to-female sex reversal in M33 mutant mice. Nature 393, 688–692 (1998).

    CAS  PubMed  Google Scholar 

  15. Katoh-Fukui, Y. et al. Cbx2, a polycomb group gene, is required for Sry gene expression in mice. Endocrinology 153, 913–924 (2012).

    CAS  PubMed  Google Scholar 

  16. Lefebvre, V., Dumitriu, B., Penzo-Mendez, A., Han, Y. & Pallavi, B. Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int. J. Biochem. Cell Biol. 39, 2195–2214 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sarkar, A. & Hochedlinger, K. The Sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12, 15–30 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Chew, L. J. & Gallo, V. The Yin and Yang of Sox proteins: activation and repression in development and disease. J. Neurosci. Res. 87, 3277–3287 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sinclair, A. H. et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346, 240–244 (1990).

    CAS  PubMed  Google Scholar 

  20. Berta, P. et al. Genetic evidence equating SRY and the testis-determining factor. Nature 348, 448–450 (1990).

    CAS  PubMed  Google Scholar 

  21. Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P. & Lovell-Badge, R. Male development of chromosomally female mice transgenic for Sry. Nature 351, 117–121 (1991).

    CAS  PubMed  Google Scholar 

  22. Koopman, P., Munsterberg, A., Capel, B., Vivian, N. & Lovell-Badge, R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348, 450–452 (1990).

    CAS  PubMed  Google Scholar 

  23. Hacker, A., Capel, B., Goodfellow, P. & Lovell-Badge, R. Expression of Sry, the mouse sex determining gene. Development 121, 1603–1614 (1995).

    CAS  PubMed  Google Scholar 

  24. Kent, J., Wheatley, S. C., Andrews, J. E., Sinclair, A. H. & Koopman, P. A male-specific role for SOX9 in vertebrate sex determination. Development 122, 2813–2822 (1996).

    CAS  PubMed  Google Scholar 

  25. Morais da Silva, S. et al. Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nat. Genet. 14, 62–68 (1996).

    CAS  PubMed  Google Scholar 

  26. Sekido, R., Bar, I., Narvaez, V., Penny, G. & Lovell-Badge, R. SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Dev. Biol. 274, 271–279 (2004).

    CAS  PubMed  Google Scholar 

  27. Chaboissier, M. C. et al. Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development 131, 1891–1901 (2004).

    CAS  PubMed  Google Scholar 

  28. Barrionuevo, F. et al. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol. Reprod. 74, 195–201 (2006).

    CAS  PubMed  Google Scholar 

  29. Bishop, C. E. et al. A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse. Nat. Genet. 26, 490–494 (2000).

    CAS  PubMed  Google Scholar 

  30. Vidal, V. P., Chaboissier, M. C., de Rooij, D. G. & Schedl, A. Sox9 induces testis development in XX transgenic mice. Nat. Genet. 28, 216–217 (2001).

    CAS  PubMed  Google Scholar 

  31. Barrionuevo, F. 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. 327, 301–312 (2009).

    CAS  PubMed  Google Scholar 

  32. Gordon, C. T. et al. Long-range regulation at the SOX9 locus in development and disease. J. Med. Genet. 46, 649–656 (2009).

    CAS  PubMed  Google Scholar 

  33. Poirier, C. et al. A complex interaction of imprinted and maternal-effect genes modifies sex determination in Odd Sex (Ods) mice. Genetics 168, 1557–1562 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mead, T. J. et al. A far-upstream (70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. Nucleic Acids Res. 41, 4459–4469 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Arango, N. A., Lovell-Badge, R. & Behringer, R. R. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 99, 409–419 (1999).

    CAS  PubMed  Google Scholar 

  36. Wilson, M. J., Jeyasuria, P., Parker, K. L. & Koopman, P. The transcription factors steroidogenic factor1 and SOX9 regulate expression of Vanin1 during mouse testis development. J. Biol. Chem. 280, 5917–5923 (2005).

    CAS  PubMed  Google Scholar 

  37. Wilhelm, D. et al. SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J. Biol. Chem. 282, 10553–10560 (2007).

    CAS  PubMed  Google Scholar 

  38. Bradford, S. T. et al. The cerebellin 4 precursor gene is a direct target of SRY and SOX9 in mice. Biol. Reprod. 80, 1178–1188 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Meeks, J. J., Weiss, J. & Jameson, J. L. Dax1 is required for testis determination. Nat. Genet. 34, 32–33 (2003).

    CAS  PubMed  Google Scholar 

  40. Swain, A., Narvaez, V., Burgoyne, P., Camerino, G. & Lovell-Badge, R. Dax1 antagonizes Sry action in mammalian sex determination. Nature 391, 761–767 (1998).

    CAS  PubMed  Google Scholar 

  41. Bouma, G. J. et al. Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells. Development 132, 3045–3054 (2005).

    CAS  PubMed  Google Scholar 

  42. Rojek, A., Obara-Moszynska, M., Malecka, E., Slomko-Jozwiak, M. & Niedziela, M. NR0B1 (DAX1) mutations in patients affected by congenital adrenal hypoplasia with growth hormone deficiency as a new finding. J. Appl. Genet. 54, 225–30 (2013).

    PubMed  Google Scholar 

  43. Bardoni, B. et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat. Genet. 7, 497–501 (1994).

    CAS  PubMed  Google Scholar 

  44. Ludbrook, L. M. & Harley, V. R. Sex determination: a 'window' of DAX1 activity. Trends Endocrinol. Metab. 15, 116–121 (2004).

    CAS  PubMed  Google Scholar 

  45. Sock, E., Schmidt, K., Hermanns-Borgmeyer, I., Bosl, M. R. & Wegner, M. Idiopathic weight reduction in mice deficient in the high-mobility-group transcription factor Sox8. Mol. Cell. Biol. 21, 6951–6959 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. O'Bryan, M. K. et al. Sox8 is a critical regulator of adult Sertoli cell function and male fertility. Dev. Biol. 316, 359–370 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Polanco, J. C., Wilhelm, D., Davidson, T. L., Knight, D. & Koopman, P. Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development. Hum. Mol. Genet. 19, 506–516 (2010).

    CAS  PubMed  Google Scholar 

  48. Tevosian, S. G. et al. Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129, 4627–4634 (2002).

    CAS  PubMed  Google Scholar 

  49. Bradford, S. T. et al. A cell-autonomous role for WT1 in regulating Sry in vivo. Hum. Mol. Genet. 18, 3429–3438 (2009).

    CAS  PubMed  Google Scholar 

  50. Capel, B. Sex in the 90s: SRY and the switch to the male pathway. Annu. Rev. Physiol. 60, 497–523 (1998).

    CAS  PubMed  Google Scholar 

  51. de Santa Barbara, P. et al. Steroidogenic factor-1 contributes to the cyclic-adenosine monophosphate down-regulation of human SRY gene expression. Biol. Reprod. 64, 775–783 (2001).

    CAS  PubMed  Google Scholar 

  52. Pilon, N. et al. Porcine SRY promoter is a target for steroidogenic factor 1. Biol. Reprod. 68, 1098–1106 (2003).

    CAS  PubMed  Google Scholar 

  53. Kuo, C. T. et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 11, 1048–1060 (1997).

    CAS  PubMed  Google Scholar 

  54. Molkentin, J. D., Lin, Q., Duncan, S. A. & Olson, E. N. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11, 1061–1072 (1997).

    CAS  PubMed  Google Scholar 

  55. Tevosian, S. G. et al. FOG2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell 101, 729–739 (2000).

    CAS  PubMed  Google Scholar 

  56. Manuylov, N. L., Smagulova, F. O., Leach, L. & Tevosian, S. G. Ovarian development in mice requires the GATA4–FOG2 transcription complex. Development 135, 3731–3743 (2008).

    CAS  PubMed  Google Scholar 

  57. Manuylov, N. L. et al. Conditional ablation of Gata4 and Fog2 genes in mice reveals their distinct roles in mammalian sexual differentiation. Dev. Biol. 353, 229–241 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kawakami, K., Sato, S., Ozaki, H. & Ikeda, K. Six family genes–structure and function as transcription factors and their roles in development. Bioessays 22, 616–626 (2000).

    CAS  PubMed  Google Scholar 

  59. Anderson, A. M., Weasner, B. M., Weasner, B. P. & Kumar, J. P. Dual transcriptional activities of SIX proteins define their roles in normal and ectopic eye development. Development 139, 991–1000 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Fujimoto, Y. et al. Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Dev. Cell 26, 416–430 (2013).

    CAS  PubMed  Google Scholar 

  61. Bogani, D. et al. Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol. 7, e1000196 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. Sekido, R. & Lovell-Badge, R. Sex determination and SRY: down to a wink and a nudge? Trends Genet. 25, 19–29 (2009).

    CAS  PubMed  Google Scholar 

  63. Gierl, M. S., Gruhn, W. H., von Seggern, A., Maltry, N. & Niehrs, C. GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. Dev. Cell 23, 1032–1042 (2012).

    CAS  PubMed  Google Scholar 

  64. Warr, N. et al. Gadd45γ and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev. Cell 23, 1020–1031 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Hoffmeyer, A., Piekorz, R., Moriggl, R. & Ihle, J. N. Gadd45γ is dispensable for normal mouse development and Tcell proliferation. Mol. Cell. Biol. 21, 3137–3143 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Nef, S. et al. Testis determination requires insulin receptor family function in mice. Nature 426, 291–295 (2003).

    CAS  PubMed  Google Scholar 

  67. Pitetti, J. L. et al. Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice. PLoS Genet. 9, e1003160 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Foster, J. W. et al. Evolution of sex determination and the Y chromosome: SRY-related sequences in marsupials. Nature 359, 531–533 (1992).

    CAS  PubMed  Google Scholar 

  69. Graves, J. A. From brain determination to testis determination: evolution of the mammalian sex-determining gene. Reprod. Fertil. Dev. 13, 665–672 (2001).

    CAS  PubMed  Google Scholar 

  70. Hughes, J. F. et al. Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes. Nature 483, 82–86 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Murtagh, V. J. et al. Evolutionary history of novel genes on the tammar wallaby Y chromosome: implications for sex chromosome evolution. Genome Res. 22, 498–507 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Laumonnier, F. et al. Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am. J. Hum. Genet. 71, 1450–1455 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Sutton, E. et al. Identification of SOX3 as an XX male sex reversal gene in mice and humans. J. Clin. Invest. 121, 328–341 (2011).

    CAS  PubMed  Google Scholar 

  74. Briscoe, J. & Therond, P. P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416–429 (2013).

    PubMed  Google Scholar 

  75. Bitgood, M. J., Shen, L. & McMahon, A. P. Sertoli cell signaling by desert hedgehog regulates the male germline. Curr. Biol. 6, 298–304 (1996).

    CAS  PubMed  Google Scholar 

  76. Yao, H. H., Whoriskey, W. & Capel, B. Desert hedgehog/patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev. 16, 1433–1440 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Beverdam, A. & Koopman, P. Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes. Hum. Mol. Genet. 15, 417–431 (2006).

    CAS  PubMed  Google Scholar 

  78. Clark, A. M., Garland, K. K. & Russell, L. D. 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. 63, 1825–1838 (2000).

    CAS  PubMed  Google Scholar 

  79. Pierucci-Alves, F., Clark, A. M. & Russell, L. D. A developmental study of the desert hedgehog-null mouse testis. Biol. Reprod. 65, 1392–1402 (2001).

    CAS  PubMed  Google Scholar 

  80. Callier, P. 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. 10, e1004340 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Ottolenghi, C. et al. Foxl2 is required for commitment to ovary differentiation. Hum. Mol. Genet. 14, 2053–2062 (2005).

    CAS  PubMed  Google Scholar 

  82. Pailhoux, E. et al. A 11.7kb deletion triggers intersexuality and polledness in goats. Nat. Genet. 29, 453–458 (2001).

    CAS  PubMed  Google Scholar 

  83. Boulanger, L. et al. FOXL2 is a female sex-determining gene in the goat. Curr. Biol. 24, 404–408 (2014).

    CAS  PubMed  Google Scholar 

  84. Uhlenhaut, N. H. et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142 (2009).

    CAS  PubMed  Google Scholar 

  85. Chassot, A. A. et al. Activation of β-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum. Mol. Genet. 17, 1264–1277 (2008).

    CAS  PubMed  Google Scholar 

  86. Maatouk, D. M. et al. Stabilization of β-catenin in XY gonads causes male-to-female sex-reversal. Hum. Mol. Genet. 17, 2949–2955 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Blecher, S. R. & Erickson, R. P. Genetics of sexual development: a new paradigm. Am. J. Med. Genet. A 143A, 3054–3068 (2007).

    CAS  PubMed  Google Scholar 

  88. Biason-Lauber, A. WNT4, RSPO1, and FOXL2 in sex development. Semin. Reprod. Med. 30, 387–395 (2012).

    CAS  PubMed  Google Scholar 

  89. McElreavey, K., Vilain, E., Abbas, N., Herskowitz, I. & Fellous, M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc. Natl Acad. Sci. USA 90, 3368–3372 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Matson, C. K. et al. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476, 101–104 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Minkina, A. et al. DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev. Cell 29, 511–520 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Takasawa, K. et al. FOXL2 transcriptionally represses Sf1 expression by antagonizing WT1 during ovarian development in mice. FASEB J. 28, 2020–2028 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Piprek, R. P. Genetic mechanisms underlying male sex determination in mammals. J. Appl. Genet. 50, 347–360 (2009).

    CAS  PubMed  Google Scholar 

  94. Kim, Y. et al. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. 4, e187 (2006).

    PubMed  PubMed Central  Google Scholar 

  95. Jameson, S. A., Lin, Y. T. & Capel, B. Testis development requires the repression of Wnt4 by Fgf signaling. Dev. Biol. 370, 24–32 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Real, F. M. et al. A microRNA (mmumiR124) prevents Sox9 expression in developing mouse ovarian cells. Biol. Reprod. 89, 78 (2013).

    PubMed  Google Scholar 

  97. Rakoczy, J. et al. MicroRNAs1405p/140–143p modulate Leydig cell numbers in the developing mouse testis. Biol. Reprod. 88, 143 (2013).

    PubMed  Google Scholar 

  98. Raymond, C. S., Murphy, M. W., O'Sullivan, M. G., Bardwell, V. J. & Zarkower, D. Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 14, 2587–2595 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Warr, N. et al. Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1. PLoS ONE 6, e19572 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Weiss, J. et al. Sox3 is required for gonadal function, but not sex determination, in males and females. Mol. Cell. Biol. 23, 8084–8091 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bouma, G. J., Washburn, L. L., Albrecht, K. H. & Eicher, E. M. Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc. Natl Acad. Sci. USA 104, 14994–14999 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Tomizuka, K. et al. R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum. Mol. Genet. 17, 1278–1291 (2008).

    CAS  PubMed  Google Scholar 

  103. Vainio, S., Heikkila, M., Kispert, A., Chin, N. & McMahon, A. P. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' research work was supported by The National Health and Medical Research Council, Australia (program grant #546517 and project grant #1031214); the Helen Macpherson Smith Trust (partnership grant #6846); the Ian Potter Centre for Genomics and Personalised Medicine; and the Victorian Government's Operational Infrastructure Support Program.

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Andrew Sinclair.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eggers, S., Ohnesorg, T. & Sinclair, A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol 10, 673–683 (2014). https://doi.org/10.1038/nrendo.2014.163

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.163

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing