The makings of maleness: Towards an integrated view of male sexual development

Nature Reviews Genetics

Volumn 7, Issue 8, 2006, Pages 620-631

  Wilhelm, Dagmar ^a   Koopman, Peter ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN; CELL DIFFERENTIATION; DEVELOPMENTAL DISORDER; EMBRYONIC STRUCTURES; ENDOTHELIUM CELL; GENITAL SYSTEM; GERM CELL; GONAD; HUMAN; LEYDIG CELL; MALE GENITAL SYSTEM; NONHUMAN; PRIORITY JOURNAL; PROSTATE; REVIEW; SERTOLI CELL; SEX DIFFERENCE; SEXUAL DEVELOPMENT; SRY GENE; TESTIS DESCENT; TESTIS DEVELOPMENT;

ANIMALS; FEMALE; GENITALIA, MALE; HUMANS; MALE; SEXUAL DEVELOPMENT;

MAMMALIA;

EID: 33746238856     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg1903     Document Type: Review

References (119)

1. Jost, A. Recherches sur la differentiation sexuelle de l'embryon de lapin. Arch. Anat. Microsc. Morphol. Exp. 36, 271-315 (1947) (in French).
2. Gubbay, J. et al. 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, 245-250 (1990).
3. 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).
4. Miyamoto, N., Yoshida, M., Kuratani, S., Matsuo, I. & Aizawa, S. Defects of urogenital development in mice lacking Emx2. Development 124, 1653-1664 (1997).
5. 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).
6. Birk, O. et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature 403, 909-913 (2000).
7. Achermann, J. C., Ito, M., Ito, M., Hindmarsh, P. C. & Jameson, J. L. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nature Genet. 22, 125-126 (1999).
8. Achermann, J. et al. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose dependent manner. J. Clin. Endocrinol. Metab. 87, 1829-1833 (2002).
9. Ozisik, G., Achermann, J. C. & Jameson, J. L. The role of SF1 in adrenal and reproductive function: insight from naturally occurring mutations in humans. Mol. Genet. Metab. 76, 85-91 (2002).
10. Englert, C. WT1 - more than a transcription factor? Trends Biochem. Sci. 23, 389-393 (1998).
11. Ludbrook, L. M. & Harley, V. R. Sex determination: a 'window' of DAX1 activity. Trends Endocrinol. Metab. 15, 116-121 (2004).
12. Berta, P. et al. Genetic evidence equating SRY and the male sex determining gene. Nature 348, 448-450 (1990).
13. Jäger, R. J., Anvret, M., Hall, K. & Scherer, G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348, 452-454 (1990).
14. 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).
15. Wilhelm, D. et al. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev. Biol. 287, 111-124 (2005). This work includes the generation and characterization of the first antibody to mouse SRY.
16. Bullejos, M. & Koopman, P. Spatially dynamic expression of Sry in mouse genital ridges. Dev. Dyn. 221, 201-205 (2001).
17. Nef, S. et al. Testis determination requires insulin receptor family function in mice. Nature 426, 291-295 (2003).
18. 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).
19. Parma, P., Pailhoux, E. & Cotinot, C. Reverse transcription- polymerase chain reaction analysis of genes involved in gonadal differentiation in pigs. Biol. Reprod. 61, 741-748 (1999).
20. Salas-Cortes, L. et al. The human SRY protein is present in fetal and adult Sertoli cells and germ cells. Int. J. Dev. Biol. 43, 135-140 (1999).
21. Harry, J. L., Koopman, P., Brennan, F. E., Graves, J. A. M. & Renfree, M. B. Widespread expression of the testis-determining gene SRY in a marsupial. Nature Genet. 11, 347-349 (1995).
22. Eicher, E. M., Washburn, L. L., Whitney, J. B. & Morrow, K. E. Mus poschiavinus Y chromosome in the C57BL/6J murine genome causes sex reversal. Science 217, 535-537 (1982).
23. DOM sex reversal. Dev. Biol. 278, 473-481 (2005).
24. Taketo, T. et al. Expression of SRY proteins in both normal and sex-reversed XY fetal mouse gonads. Dev. Dyn. 233, 612-622 (2005).
25. Nagamine, C., Morohashi, K., Carlisle, C. & Chang, D. Sex reversal caused by Mus musculus domesticus Y chromosomes linked to variant expression of the testis-determining gene Sry. Dev. Biol. 216, 182-194 (1999).
26. Hoffenberg, R. & Jackson, W. P. Gonadal dysgenesis: modern concepts. BMJ 29, 1457-1462 (1957).
27. Pontiggia, A. et al. Sex-reversing mutations affect the architecture of SRY-DNA complexes. EMBO J. 13, 6115-6124 (1994).
28. Schmitt-Ney, M. et al. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am. J. Hum. Genet. 56, 862-869 (1995).
29. Jäger, R., Harley, V., Pfeiffer, R., Goodfellow, P. & Scherer, G. A familial mutation in the testis-determining gene SRY shared by both sexes. Hum. Genet. 90, 350-355 (1992).
30. Harley, V. R. et al. DNA binding activity of recombinant SRY from normal males and XY females. Science 255, 453-456 (1992).
31. Baldazzi, L. et al. Two new point mutations of the SRY gene identified in two Italian 46,XY females with gonadal dysgenesis. Clin. Genet. 64, 258-260 (2003).
32. Shahid, M. et al. Two new novel point mutations localized upstream and downstream of the HMG box region of the SRY gene in three Indian 46,XY females with sex reversal and gonadal tumour formation. Mol. Hum. Reprod. 10, 521-526 (2004).
33. Shahid, M., Dhillon, V. S., Aslam, M. & Husain, S. A. Three new novel point mutations localized within and downstream of high-mobility group-box region in SRY gene in three Indian females with Turner syndrome. J. Clin. Endocrinol. Metab. 90, 2429-2435 (2005).
34. McElreavey, K., Vilain, E., 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).
35. Burgoyne, P. S., Buehr, M., Koopman, P., Rossant, J. & McLaren, A. Cell-autonomous action of the testis-determining gene: Sertoli cells are exclusively XY in XX-XY chimaeric mouse testes. Development 102, 443-450 (1988).
36. Adams, I. & McLaren, A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis. Development 129, 1155-1164 (2002).
37. Malki, S. et al. Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. EMBO J. 24, 1798-1809 (2005).
38. 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).
39. 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. Nature Genet. 14, 62-68 (1996).
40. Schepers, G., Wilson, M., Wilhelm, D. & Koopman, P. SOX8 is expressed during testis differentiation in mice and synergizes with SF1 to activate the Amh promoter in vitro. J. Biol. Chem. 278, 28101-28108 (2003).
41. Foster, J. W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature 372, 525-530 (1994).
42. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111-1120 (1994).
43. Vidal, V., Chaboissier, M., de Rooij, D. & Schedl, A. Sox9 induces testis development in XX transgenic mice. Nature Genet. 28, 216-217 (2001).
44. Huang, B., Wang, S., Ning, Y., Lamb. A. & Bartley, J. Autosomal XX sex reversal caused by duplication of SOX9. Am. J. Med. Genet. 87, 349-353 (1999).
45. Bishop, C. E. et al. A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse. Nature Genet. 26, 490-494 (2000).
46. Chaboissier, M. C. et al. Functional analysis of Sox8 and Sox9 during sex determination in the mouse. Development 131, 1891-901 (2004).
47. Barrionuevo, F. et al. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol. Reprod. 74, 195-201 (2006). References 46 and 47 showed for the first time that null mutation of Sox9 results in complete XY sex reversal in mice.
48. DeFalco, T. J. et al. Sex-specific apoptosis regulates sexual dimorphism in the Drosophila embryonic gonad. Dev. Cell 5, 205-216 (2003).
49. Capel, B. The battle of the sexes. Mech. Dev. 92, 89-103 (2000).
50. Swain, A. & Lovell-Badge, R. Mammalian sex determination: a molecular drama. Genes Dev. 13, 755-767 (1999).
51. Schmahl, J., Eicher, E., Washburn, L. & Capel, B. Sry induces cell proliferation in the mouse gonad. Development 127, 65-73 (2000).
52. Capel, B., Albrecht, K. H., Washburn, L. L. & Eicher, E. M. Migration of mesonephric cells into the mammalian gonad depends on Sry. Mech. Dev. 84, 127-131 (1999).
53. Martineau, J., Nordqvist, K., Tilmann, C., Lovell-Badge, R. & Capel, B. Male-specific cell migration into the developing gonad. Curr. Biol. 7, 958-968 (1997).
54. Cupp, A. S., Kim, G. H. & Skinner, M. K. Expression and action of neurotropin-3 and nerve growth factor in embryonic and early postnatal rat testis development. Biol. Reprod. 63, 1617-1628 (2000).
55. Ricci, G., Catizone, A. & Galderi, M. Pleiotropic activity of hepatocyte growth factor during embryonic testis development. Mech. Dev. 118, 19-28 (2002).
56. Smith, C. A., McClive, P. J., Hudson, Q. & Sinclair, A. H. Male-specific cell migration into the developing gonad is a conserved process involving PDGF signalling. Dev. Biol. 284, 337-350 (2005).
57. Buehr, M., Gu, S. & McLaren, A. Mesonephric contribution to testis differentiation in the fetal mouse. Development 117, 273-281 (1993).
58. Jeanes, A. et al. Evaluation of candidate markers for the peritubular myoid cell lineage in the developing mouse testis. Reproduction 130, 509-516 (2005).
59. 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).
60. Bitgood, M. J., Shen, L. & McMahon, A. P. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr. Biol. 6, 298-304 (1996).
61. Pierucci-Alves, F., Clark, A. & Russell, L. A developmental study of the Desert hedgehog-null mouse testis. Biol. Reprod. 65, 1392-1402 (2001).
62. Canto, P., Vilchis, F., Soderlund, D., Reyes, E. & Mendez, J. P. A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis. Mol. Hum. Reprod. 11, 833-836 (2005).
63. Canto, P., Soderlund, D., Reyes, E. & Mendez, J. P. Mutations in the Desert hedgehog (DHH) gene in patients with 46,XY complete pure gonadal dysgenesis. J. Clin. Endocrinol. Metab. 89, 4480-4483 (2004).
64. Umehara, F., Tate, G., Itoh, K. & Osame, M. Minifascicular neuropathy: a new concept of the human disease caused by Desert hedgehog gene mutation. Cell. Mol. Biol. 48, 187-189 (2002).
65. Brennan, J., Karl, J. & Capel, B. Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad. Dev. Biol. 244, 418-428 (2002).
66. Bullejos, M., Bowles, J. & Koopman, P. Extensive vascularization of developing mouse ovaries revealed by caveolin-1 expression. Dev. Dyn. 225, 95-99 (2002).
67. Jeays-Ward, K. et al. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 130, 3663-3670 (2003).
68. Kitamura, K. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genet. 32, 359-369 (2002).
69. Kato, M. et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum. Mutat. 23, 147-159 (2004).
70. Tang, P., Park, D. J., Marshall Graves, J. A. & Harley, V. R. ATRX and sex differentiation. Trends Endocrinol. Metab. 15, 339-344 (2004).
71. Brennan, J., Tilmann, C. & Capel, B. Pdgfr-α mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev. 17, 800-810 (2003).
72. Gnessi, L. et al. Leydig cell loss and spermatogenic arrest in platelet-derived growth factor (PDGF)-A-deficient mice. J. Cell Biol. 149, 1019-1026 (2000).
73. Tanaka, S. S., Yamaguchi, Y. L., Tsoi, B., Lickert, H. & Tam, P. P. IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion. Dev. Cell 9, 745-756 (2005).
74. Molyneaux, K. A. et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130, 4279-4286 (2003).
75. McLaren, A. & Southee, D. Entry of mouse embryonic germ cells into meiosis. Dev. Biol. 187, 107-113 (1997).
76. Hilscher, B. et al. Kinetics of gametogenesis. I. Comparative histological and autoradiographic studies of oocytes and transitional prospermatogonia during oogenesis and prespermatogenesis. Cell Tissue Res. 154, 443-470 (1974).
77. McLaren, A. Germ and somatic cell lineages in the developing gonad. Mol. Cell. Endocrinol. 163, 3-9 (2000).
78. Koubova, J. et al. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc. Natl Acad. Sci. USA 103, 2474-2479 (2006).
79. Bowles, J. et al. Retinoid signaling determines germ cell fate in mice. Science 312, 596-600 (2006). References 78 and 79 provide evidence that the entry into meiosis is not a cell-autonomous property of germ cells, but is induced by retinoic acid.
80. Kurohmaru, M., Kanai, Y. & Hayashi, Y. A cytological and cytoskeletal comparison of Sertoli cells without germ cell and those with germ cells using the W/WV mutant mouse. Tissue Cell 24, 895-903 (1992).
81. Adham, I. M. & Agoulnik, A. I. Insulin-like 3 signalling in testicular descent. Int. J. Androl. 27, 257-265 (2004).
82. Kaleva, M. & Toppari, J. Cryptorchidism: an indicator of testicular dysgenesis? Cell Tissue Res. 322, 167-172 (2005).
83. Ivell, R. & Hartung, S. The molecular basis of cryptorchidism. Mol. Hum. Reprod. 9, 175-181 (2003).
84. Hutson, J. M., Hasthorpe, S. & Heyns, C. F. Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr. Rev. 18, 259-280 (1997).
85. Roberts, L. M., Visser, J. A. & Ingraham, H. A. Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development. Development 129, 1487-1496 (2002).
86. Imbeaud, S. et al. Molecular genetics of the persistent mullerian duct syndrome: a study of 19 families. Hum. Mol. Genet. 3, 125-131 (1994).
87. Hoshiya, M. et al. Persistent Mullerian duct syndrome caused by both a 27-bp deletion and a novel splice mutation in the MIS type II receptor gene. Birth Defects Res. A 67, 868-874 (2003).
88. Behringer, R. R. The in vivo roles of mullerian-inhibiting substance. Curr. Top. Dev. Biol. 29, 171-187 (1994).
89. Chen, M. Y., Carpenter, D. & Zhao, G. Q. Expression of bone morphogenetic protein 7 in murine epididymis is developmentally regulated. Biol. Reprod. 60, 1503-1508 (1999).
90. Hu, J. et al. Developmental expression and function of Bmp4 in spermatogenesis and in maintaining epididymal integrity. Dev. Biol. 276, 158-171 (2004).
91. Zhao, G. Q., Chen, Y. X., Liu, X. M., Xu, Z. & Qi, X. Mutation in Bmp7 exacerbates the phenotype of Bmp8a mutants in spermatogenesis and epididymis. Dev. Biol. 240, 212-222 (2001).
92. Settle, S. et al. The BMP family member Gdf7 is required for seminal vesicle growth, branching morphogenesis, and cytodifferentiation. Dev. Biol. 234, 138-150 (2001).
93. Benson, G. V. et al. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development 122, 2687-2696 (1996).
94. Hsieh-Li, H. M. et al. Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility. Development 121, 1373-1385 (1995).
95. Sonnenberg-Riethmacher, E., Walter, B., Riethmacher, D., Godecke, S. & Birchmeier, C. The c-ros tyrosine kinase receptor controls regionalization and differentiation of epithelial cells in the epididymis. Genes Dev. 10, 1184-1193 (1996).
96. Mendive, F. et al. Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev. Biol. 290, 421-434 (2006).
97. Samuel, C. S. et al. The relaxin gene-knockout mouse: a model of progressive fibrosis. Ann. NY Acad. Sci. 1041, 173-181 (2005).
98. Basciani, S. et al. Expression of platelet-derived growth factor (PDGF) in the epididymis and analysis of the epididymal development in PDGF-A, PDGF-B, and PDGF receptor β deficient mice. Biol. Reprod. 70, 168-177 (2004).
99. Cuppens, H. & Cassiman, J. J. CFTR mutations and polymorphisms in male infertility. Int. J. Androl. 27, 251-256 (2004).
100. Hildebrand, M. Reproductive Systems and Urogenital Ducts. Analysis of Vertebrate Structures (John Wiley & Sons Inc., New York, 1995).
101. Cobb, J. & Duboule, D. Comparative analysis of genes downstream of the Hoxd cluster in developing digits and external genitalia. Development 132, 3055-3067 (2005). This study investigated whether a similar Hox expression pattern in distinct tissues leads to the modulation of the same or different target genes.
102. Villee, D. B. & Crigler, J. F. Jr. The adrenogenital syndrome. Clin. Perinatol. 3, 211-220 (1976).
103. Pinsky, L., Erickson, R. P. & Schimke, R. N. Genetic Disorders of Human Sexual Development (Oxford Univ. Press, New York, 1999).
104. Dravis, C. et al. Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev. Biol. 271, 272-290 (2004). This paper suggests for the first time that impaired transaction of both forward and reverse components of Eph-ephrin signalling can lead to hypospadias in mice.
105. Goodman, F. R. et al. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am. J. Hum. Genet. 67, 197-202 (2000).
106. Grier, D. G. et al. The pathophysiology of HOX genes and their role in cancer. J. Pathol. 205, 154-171 (2005).
107. Innis, J. W. et al. Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model. Hum. Mol. Genet. 13, 2841-2851 (2004).
108. Manson, J. M. & Carr, M. C. Molecular epidemiology of hypospadias: review of genetic and environmental risk factors. Birth Defects Res. A 67, 825-836 (2003).
109. Cunha, G. R. et al. The endocrinology and developmental biology of the prostate. Endocr. Rev. 8, 338-362 (1987).
110. Timms, B. G., Mohs, T. J. & Didio, L. J. Ductal budding and branching patterns in the developing prostate. J. Urol. 151, 1427-1432 (1994).
111. Marker, P. C., Donjacour, A. A., Dahiya, R. & Cunha, G. R. Hormonal, cellular, and molecular control of prostate development. Dev. Biol. 253, 165-174 (2003). This paper provides an excellent overview of the development of the prostate.
112. Zhang, T. J., Hoffman, B. G., Ruiz de Algara, T. & Helgason, C. D. SAGE reveals expression of Wnt signalling pathway members during mouse prostate development. Gene Expr. Patterns 6, 310-324 (2006).
113. Dewing, P., Shi, T., Horvath, S. & Vilain, E. Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Brain Res. Mol. Brain Res. 118, 82-90 (2003).
114. De Vries, G. J. et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J. Neurosci. 22, 9005-9014 (2002).
115. Clépet, C. et al. The human SRY transcript. Hum. Mol. Genet. 2, 2007-2012 (1993).
116. Lahr G. et al. Transcription of the Y chromosomal gene. Sry, in adult mouse brain. Brain Res. Mol. Brain Res. 33, 179-182 (1995).
117. Mayer, A., Lahr, G., Swaab, D., Pilgrim, C. & Reisert, I. The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics 281-288 (1998).
118. Mayer, A., Mosler, G., Just, W., Pilgrim, C. & Reisert, I. Developmental profile of Sry transcripts in mouse brain. Neurogenetics 5, 25-30 (2000).
119. Dewing, P. et al. Direct regulation of adult brain function by the male-specific factor SRY. Curr. Biol. 16, 415-420 (2006). This provocative study indicates that the male-determining factor SRY has a direct role in brain sexual dimorphism.