The Reproductive System

  • Andrew PaskEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 886)


Correct sexual development is arguably the most important trait in an organism’s life history since it is directly related to its genetic fitness. The developing gonad houses the germ cells, the only legacy we pass on to subsequent generations. Given the pivotal importance of correct reproductive function, it is confounding that disorders of sex development (DSDs) are among the most common congenital abnormalities in humans (Lee et al. J Pediatr Urol 8(6):611–615, 2012). Urogenital development is a highly complex process involving coordinated interactions between molecular and hormonal pathways in a tightly regulated order. The controls that regulate some of the key events in this process are beginning to be unraveled. This chapter provides an overview of our understanding of urogenital development from the gonads to the urogenital ducts and external genitalia.


Urogenital system Testis Ovary External genitalia Mammary gland Sexual differentiation 


  1. Adriaenssens E, Lottin S, Dugimont T, Fauquette W, Coll J, Dupouy JP, Boilly B, Curgy JJ (1999) Steroid hormones modulate H19 gene expression in both mammary gland and uterus. Oncogene 18(31):4460–4473. doi: 10.1038/sj.onc.1202819 CrossRefPubMedGoogle Scholar
  2. Allgeier SH, Lin TM, Moore RW, Vezina CM, Abler LL, Peterson RE (2010) Androgenic regulation of ventral epithelial bud number and pattern in mouse urogenital sinus. Dev Dyn 239(2):373–385. doi: 10.1002/dvdy.22169 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Angiolini E, Fowden A, Coan P, Sandovici I, Smith P, Dean W, Burton G, Tycko B, Reik W, Sibley C, Constancia M (2006) Regulation of placental efficiency for nutrient transport by imprinted genes. Placenta 27(Suppl A):S98–S102, doi:S0143-4004(06)00003-8 [pii]CrossRefPubMedGoogle Scholar
  4. Barrionuevo F, Bagheri-Fam S, Klattig J, Kist R, Taketo MM, Englert C, Scherer G (2006) Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol Reprod 74(1):195–201CrossRefPubMedGoogle Scholar
  5. Behringer RR (1994) The in vivo roles of mullerian-inhibiting substance. Curr Top Dev Biol 29:171–187CrossRefPubMedGoogle Scholar
  6. Behringer RR, Finegold MJ, Cate RL (1994) Mullerian-inhibiting substance function during mammalian sexual development. Cell 79(3):415–425, doi:0092-8674(94)90251-8 [pii]CrossRefPubMedGoogle Scholar
  7. Bishop CE, Whitworth DJ, Qin Y, Agoulnik AI, Agoulnik IU, Harrison WR, Behringer RR, Overbeek PA (2000) A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Nat Genet 26(4):490–494CrossRefPubMedGoogle Scholar
  8. Borum K (1961) Oogenesis in the mouse. A study of the meiotic prophase. Exp Cell Res 24:495–507CrossRefPubMedGoogle Scholar
  9. Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312(5773):596–600, doi:1125691 [pii]CrossRefPubMedGoogle Scholar
  10. Brennan J, Capel B (2004) One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5(7):509–521. doi: 10.1038/nrg1381 CrossRefPubMedGoogle Scholar
  11. Britt KL, Kerr J, O’Donnell L, Jones ME, Drummond AE, Davis SR, Simpson ER, Findlay JK (2002) Estrogen regulates development of the somatic cell phenotype in the eutherian ovary. FASEB J 16(11):1389–1397. doi: 10.1096/fj.01-0992com CrossRefPubMedGoogle Scholar
  12. Britt KL, Saunders PK, McPherson SJ, Misso ML, Simpson ER, Findlay JK (2004) Estrogen actions on follicle formation and early follicle development. Biol Reprod 71(5):1712–1723. doi: 10.1095/biolreprod.104.028175 CrossRefPubMedGoogle Scholar
  13. Bullejos M, Bowles J, Koopman P (2002) Extensive vascularization of developing mouse ovaries revealed by caveolin-1 expression. Dev Dyn 225(1):95–99. doi: 10.1002/dvdy.10128 CrossRefPubMedGoogle Scholar
  14. Burgoyne PS, Buehr M, McLaren A (1988) XY follicle cells in ovaries of XX – XY female mouse chimaeras. Development 104(4):683–688PubMedGoogle Scholar
  15. Capel B, Albrecht KH, Washburn LL, Eicher EM (1999) Migration of mesonephric cells into the mammalian gonad depends on Sry. Mech Dev 84(1–2):127–131CrossRefPubMedGoogle Scholar
  16. Cohn MJ (2004) Developmental genetics of the external genitalia. Adv Exp Med Biol 545:149–157CrossRefPubMedGoogle Scholar
  17. Couse JF, Hewitt SC, Bunch DO, Sar M, Walker VR, Davis BJ, Korach KS (1999) Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science 286(5448):2328–2331, doi:8111 [pii]CrossRefPubMedGoogle Scholar
  18. Coveney D, Cool J, Oliver T, Capel B (2008) Four-dimensional analysis of vascularization during primary development of an organ, the gonad. Proc Natl Acad Sci U S A 105(20):7212–7217, doi:0707674105 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  19. Daniel CW, Smith GH (1999) The mammary gland: a model for development. J Mammary Gland Biol Neoplasia 4(1):3–8CrossRefPubMedGoogle Scholar
  20. Du H, Taylor HS (2004) Molecular regulation of mullerian development by Hox genes. Ann N Y Acad Sci 1034:152–165, doi:1034/1/152 [pii]CrossRefPubMedGoogle Scholar
  21. Frojdman K, Paranko J, Kuopio T, Pelliniemi LJ (1989) Structural proteins in sexual differentiation of embryonic gonads. Int J Dev Biol 33(1):99–103PubMedGoogle Scholar
  22. Gubbay J, Collignon J, Koopman P, Capel B, Economou A, Munsterberg A, Vivian N, Goodfellow P, Lovell-Badge R (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346(6281):245–250. doi: 10.1038/346245a0 CrossRefPubMedGoogle Scholar
  23. Hannema SE, Hughes IA (2007) Regulation of Wolffian duct development. Horm Res 67(3):142–151, doi:96644 [pii]PubMedGoogle Scholar
  24. Harry JL, Koopman P, Brennan FE, Graves JA, Renfree MB (1995) Widespread expression of the testis-determining gene SRY in a marsupial. Nat Genet 11(3):347–349. doi: 10.1038/ng1195-347 CrossRefPubMedGoogle Scholar
  25. Hashimoto N, Kubokawa R, Yamazaki K, Noguchi M, Kato Y (1990) Germ cell deficiency causes testis cord differentiation in reconstituted mouse fetal ovaries. J Exp Zool 253(1):61–70. doi: 10.1002/jez.1402530109 CrossRefPubMedGoogle Scholar
  26. Henkes LE, Davis JS, Rueda BR (2003) Mutant mouse models and their contribution to our knowledge of corpus luteum development, function and regression. Reprod Biol Endocrinol 1:87. doi: 10.1186/1477-7827-1-87 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Hennighausen L, Robinson GW (2005) Information networks in the mammary gland. Nat Rev Mol Cell Biol 6(9):715–725. doi: 10.1038/nrm1714 CrossRefPubMedGoogle Scholar
  28. Hens JR, Wysolmerski JJ (2005) Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res 7(5):220–224, doi:bcr1306 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hubertus J, Lacher M, Rottenkolber M, Muller-Hocker J, Berger M, Stehr M, von Schweinitz D, Kappler R (2011) Altered expression of imprinted genes in Wilms tumors. Oncol Rep 25(3):817–823. doi: 10.3892/or.2010.1113 CrossRefPubMedGoogle Scholar
  30. Josso N (1970a) Action of human testis on rat fetus Muller’s duct in organ culture. C R Acad Sci Hebd Seances Acad Sci D 271(23):2149–2152PubMedGoogle Scholar
  31. Josso N (1970b) Action of testosterone on the Wolffian duct of rat fetus in organ culture. Arch Anat Microsc Morphol Exp 59(1):37–49PubMedGoogle Scholar
  32. Ju X, Li Z, Zhang C, Qin C, Shao P, Li J, Li P, Cao Q, Zhang W, Wang Z, Yin C (2013) Clinical aspects and molecular genetics of persistent mullerian duct syndrome associated with transverse testicular ectopia: report of three cases. Urol Int 90(1):83–86, doi:000339599 [pii]CrossRefPubMedGoogle Scholar
  33. Kanai Y, Hayashi Y, Kawakami H, Takata K, Kurohmaru M, Hirano H, Nishida T (1991) Effect of tunicamycin, an inhibitor of protein glycosylation, on testicular cord organization in fetal mouse gonadal explants in vitro. Anat Rec 230(2):199–208. doi: 10.1002/ar.1092300207 CrossRefPubMedGoogle Scholar
  34. Kanai Y, Kawakami H, Takata K, Kurohmaru M, Hirano H, Hayashi Y (1992) Involvement of actin filaments in mouse testicular cord organization in vivo and in vitro. Biol Reprod 46(2):233–245CrossRefPubMedGoogle Scholar
  35. Katoh-Fukui Y, Tsuchiya R, Shiroishi T, Nakahara Y, Hashimoto N, Noguchi K, Higashinakagawa T (1998) Male-to-female sex reversal in M33 mutant mice. Nature 393(6686):688–692. doi: 10.1038/31482 CrossRefPubMedGoogle Scholar
  36. Keil KP, Mehta V, Abler LL, Joshi PS, Schmitz CT, Vezina CM (2012) Visualization and quantification of mouse prostate development by in situ hybridization. Differentiation 84(3):232–239, doi:S0301-4681(12)00106-5 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kleinman HK, Weeks BS, Schnaper HW, Kibbey MC, Yamamura K, Grant DS (1993) The laminins: a family of basement membrane glycoproteins important in cell differentiation and tumor metastases. Vitam Horm 47:162–186Google Scholar
  38. Kobayashi A, Stewart CA, Wang Y, Fujioka K, Thomas NC, Jamin SP, Behringer RR (2011) beta-Catenin is essential for Mullerian duct regression during male sexual differentiation. Development 138(10):1967–1975, doi:dev.056143 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  39. Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R (1990) Expression of a candidate sex-determining gene during mouse testis differentiation. Nature 348(6300):450–452CrossRefPubMedGoogle Scholar
  40. Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R (1991) Male development of chromosomally female mice transgenic for Sry. Nature 351(6322):117–121. doi: 10.1038/351117a0 CrossRefPubMedGoogle Scholar
  41. Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103(8):2474–2479, doi:0510813103 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  42. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R (1993) WT-1 is required for early kidney development. Cell 74(4):679–691, doi:0092-8674(93)90515-R [pii]CrossRefPubMedGoogle Scholar
  43. Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M (2013) Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 341(6150):1106–1109, doi:341/6150/1106 [pii]CrossRefPubMedGoogle Scholar
  44. Lee P, Schober J, Nordenstrom A, Hoebeke P, Houk C, Looijenga L, Manzoni G, Reiner W, Woodhouse C (2012) Review of recent outcome data of disorders of sex development (DSD): emphasis on surgical and sexual outcomes. J Pediatr Urol 8(6):611–615, doi:S1477-5131(12)00253-7 [pii]CrossRefPubMedGoogle Scholar
  45. Lovell-Badge R, Robertson E (1990) XY female mice resulting from a heritable mutation in the primary testis-determining gene, Tdy. Development 109(3):635–646PubMedGoogle Scholar
  46. Luo X, Ikeda Y, Parker KL (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77(4):481–490, doi:0092-8674(94)90211-9 [pii]CrossRefPubMedGoogle Scholar
  47. Magoffin DA (2005) Ovarian theca cell. Int J Biochem Cell Biol 37(7):1344–1349, doi:S1357-2725(05)00057-9 [pii]CrossRefPubMedGoogle Scholar
  48. Malki S, Berta P, Poulat F, Boizet-Bonhoure B (2005) Cytoplasmic retention of the sex-determining factor SOX9 via the microtubule network. Exp Cell Res 309(2):468–475, doi:S0014-4827(05)00326-5 [pii]CrossRefPubMedGoogle Scholar
  49. Martineau J, Nordqvist K, Tilmann C, Lovell-Badge R, Capel B (1997) Male-specific cell migration into the developing gonad. Curr Biol 7(12):958–968, doi:S0960-9822(06)00415-5 [pii]CrossRefPubMedGoogle Scholar
  50. Merchant H (1975) Rat gonadal and ovarioan organogenesis with and without germ cells. An ultrastructural study. Dev Biol 44(1):1–21CrossRefPubMedGoogle Scholar
  51. Merchant-Larios H, Moreno-Mendoza N, Buehr M (1993) The role of the mesonephros in cell differentiation and morphogenesis of the mouse fetal testis. Int J Dev Biol 37(3):407–415PubMedGoogle Scholar
  52. Morita Y, Manganaro TF, Tao XJ, Martimbeau S, Donahoe PK, Tilly JL (1999) Requirement for phosphatidylinositol-3′-kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse. Endocrinology 140(2):941–949CrossRefPubMedGoogle Scholar
  53. Palmer SJ, Burgoyne PS (1991) In situ analysis of fetal, prepuberal and adult XX – XY chimaeric mouse testes: Sertoli cells are predominantly, but not exclusively, XY. Development 112(1):265–268PubMedGoogle Scholar
  54. Pask AJ, Calatayud NE, Shaw G, Wood WM, Renfree MB (2010) Oestrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal. BMC Biol 8(1):113, doi:1741-7007-8-113 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  55. Paulsson M (1992) Basement membrane proteins: structure, assembly, and cellular interactions. Crit Rev Biochem Mol Biol 27(1–2):93–127. doi: 10.3109/10409239209082560 PubMedGoogle Scholar
  56. Payne AH, Hardy MP, Russell LD (1996) The Leydig cell. Cache River Press, ViennaGoogle Scholar
  57. Pelliniemi LJ, Frojdman K (2001) Structural and regulatory macromolecules in sex differentiation of gonads. J Exp Zool 290(5):523–528. doi: 10.1002/jez.1096 CrossRefPubMedGoogle Scholar
  58. Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn MJ (2002) Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol 247(1):26–46. doi: 10.1006/dbio.2002.0668 CrossRefPubMedGoogle Scholar
  59. Qin Y, Bishop CE (2005) Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry. Hum Mol Genet 14(9):1221–1229CrossRefPubMedGoogle Scholar
  60. Qin Y, Kong LK, Poirier C, Truong C, Overbeek PA, Bishop CE (2004) Long-range activation of Sox9 in Odd Sex (Ods) mice. Hum Mol Genet 13(12):1213–1218. doi: 10.1093/hmg/ddh141 CrossRefPubMedGoogle Scholar
  61. Renfree MB, Ager EI, Shaw G, Pask AJ (2008) Genomic imprinting in marsupial placentation. Reproduction 136(5):523–531, doi:REP-08-0264 [pii]CrossRefPubMedGoogle Scholar
  62. Renfree MB, Suzuki S, Kaneko-Ishino T (2013) The origin and evolution of genomic imprinting and viviparity in mammals. Philos Trans R Soc Lond B Biol Sci 368(1609):20120151, doi:rstb.2012.0151 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  63. Richardson LL, Kleinman HK, Dym M (1995) Basement membrane gene expression by Sertoli and peritubular myoid cells in vitro in the rat. Biol Reprod 52(2):320–330CrossRefPubMedGoogle Scholar
  64. Rossi P, Dolci S, Albanesi C, Grimaldi P, Geremia R (1993) Direct evidence that the mouse sex-determining gene Sry is expressed in the somatic cells of male fetal gonads and in the germ cell line in the adult testis. Mol Reprod Dev 34(4):369–373CrossRefPubMedGoogle Scholar
  65. Schmahl J, Capel B (2003) Cell proliferation is necessary for the determination of male fate in the gonad. Dev Biol 258(2):264–276CrossRefPubMedGoogle Scholar
  66. Schmahl J, Eicher EM, Washburn LL, Capel B (2000) Sry induces cell proliferation in the mouse gonad. Development 127(1):65–73PubMedGoogle Scholar
  67. Sekido R, Lovell-Badge R (2008) Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453(7197):930–934, doi:nature06944 [pii]CrossRefPubMedGoogle Scholar
  68. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O et al (1995) Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204(1):22–29. doi: 10.1002/aja.1002040104 CrossRefPubMedGoogle Scholar
  69. Siegel PM, Muller WJ (2010) Transcription factor regulatory networks in mammary epithelial development and tumorigenesis. Oncogene 29(19):2753–2759, doi:onc201043 [pii]CrossRefPubMedGoogle Scholar
  70. Stringer JM, Suzuki S, Pask AJ, Shaw G, Renfree MB (2012a) Promoter-specific expression and imprint status of marsupial IGF2. PLoS One 7(7):e41690. doi: 10.1371/journal.pone.0041690 CrossRefPubMedPubMedCentralGoogle Scholar
  71. Stringer JM, Suzuki S, Pask AJ, Shaw G, Renfree MB (2012b) Selected imprinting of INS in the marsupial. Epigenetics Chromatin 5(1):14, doi:1756-8935-5-14 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  72. Svingen T, Koopman P (2007) Involvement of homeobox genes in mammalian sexual development. Sex Dev 1(1):12–23, doi:96235 [pii]CrossRefPubMedGoogle Scholar
  73. Timpl R (1993) Proteoglycans of basement membranes. Experientia 49(5):417–428CrossRefPubMedGoogle Scholar
  74. Tung PS, Fritz IB (1993) Interactions of Sertoli cells with laminin are essential to maintain integrity of the cytoskeleton and barrier functions of cells in culture in the two-chambered assembly. J Cell Physiol 156(1):1–11. doi: 10.1002/jcp.1041560102 CrossRefPubMedGoogle Scholar
  75. Tyndale-Biscoe CH, Renfree MB (1987) Reproductive physiology of marsupials, Monographs on marsupial biology. Cambridge University Press, Cambridge/New YorkCrossRefGoogle Scholar
  76. Vidal VP, Chaboissier MC, de Rooij DG, Schedl A (2001) Sox9 induces testis development in XX transgenic mice. Nat Genet 28(3):216–217CrossRefPubMedGoogle Scholar
  77. Wilhelm D, Martinson F, Bradford S, Wilson MJ, Combes AN, Beverdam A, Bowles J, Mizusaki H, Koopman P (2005) Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev Biol 287(1):111–124CrossRefPubMedGoogle Scholar
  78. Wilhelm D, Palmer S, Koopman P (2007) Sex determination and gonadal development in mammals. Physiol Rev 87(1):1–28. doi: 10.1152/physrev.00009.2006, 87/1/1 [pii]CrossRefPubMedGoogle Scholar
  79. Yamada G (2005) Reproductive/urogenital organ development and molecular genetic cascades: glamorous developmental processes of bodies. J Biochem 137(6):665–669. doi: 10.1093/jb/mvi085, 137/6/665 [pii]CrossRefPubMedGoogle Scholar
  80. Yamada G, Suzuki K, Haraguchi R, Miyagawa S, Satoh Y, Kamimura M, Nakagata N, Kataoka H, Kuroiwa A, Chen Y (2006) Molecular genetic cascades for external genitalia formation: an emerging organogenesis program. Dev Dyn 235(7):1738–1752. doi: 10.1002/dvdy.20807 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.School of BioSciencesThe University of MelbourneMelbourneAustralia

Personalised recommendations