Subscribe to RSS
DOI: 10.1055/s-2000-13474
Sexual Differentiation
Publication History
Publication Date:
31 December 2000 (online)
ABSTRACT
Sexual differentiation in humans is genetically and hormonally controlled. In response to a signal from a dominant-acting gene on the Y chromosome, primordial cells in the embryonic gonad ridge differentiate into Sertoli cells and affect newly migrated germ cells to differentiate as spermatogonia, thus creating a testis. The cells of the embryonic testis secrete hormones that lead to the development of most, if not all, male secondary sexual characteristics. The Sertoli cells secrete müllerian inhibitory factor (MIF), causing regression of the müllerian ducts and of stray oogonia. The Leydig cells secrete testosterone, causing differentiation and growth of the wolffian duct structures. Dihydrotestosterone, created by metabolism of testosterone, causes growth of the prostate and phallus and fusion of the labioscrotal folds. In the absence of SRY, Sertoli cell differentiation does not occur. Rather germ cells migrating into the primordial gonad differentiate as oogonia and cause interstitial cells to differentiate as granulosa cells. In the absence of MIF and testosterone, the müllerian ducts differentiate and grow as female internal genitalia and the external genitalia are feminized. Several genes have been identified that control testis determination. These include SRY, WT1, SOX9, SF1, XH2, and DAX1. Most of these genes were discovered by analysis of rare cases of sex reversal (genetic sex of one type, gonadal sex of the other type).
KEYWORD
determination - gonadal differentiation - intersex conditions - gonadal dysgenesis - hermaphroditism
REFERENCES
- 1 Capel B. The battle of the sexes. Mech Dev . 2000; 92 89-103
- 2 Roberts L M, Shen J, Ingraham H A. New solutions to an ancient riddle: defining the differences between Adam and Eve. Am J Hum Genet . 1999; 65 933-942
- 3 Jost A, Vigier B, Prepin J, Perchellet J P. Studies of sex determination in mammals. Recent Prog Horm Res . 1973; 29 1-41
- 4 Sarafoglou K, Ostrer H. Familial sex reversal: a review. J Clin Endocrinol Metab . 2000; 85 483-493
- 5 Jirasek J E. Morphogenesis of the genital system in the human. Birth Defects . 1977; 13 13-39
- 6 Singh R P, Carr D H. The anatomy and histology of XO human embryos and fetuses. Anat Rec . 1966; 155 369-383
- 7 Baker T G. A quantitative and cytological study of germ cells in human primordial oocytes. Proc R Soc Lond Biol Sci . 1963; 158 417-433
- 8 Baker T G, Franchi L L. The fine structure of oogonia and oocytes in human ovaries. J Cell Sci . 1967; 2 213-224
- 9 Ginsburg M, Snow M HL, McLaren A. Primordial germ cells in the mouse embryo during gastrulation. Development . 1990; 110 521-528
- 10 Witschi E. Migration of the germ cells of human embryos from the yolk sac to the primitive gonadal folds. Contrib Embryol Carnegie Inst Wash . 1948; 32 67-80
- 11 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 . 1988; 102 443-450
- 12 Francavilla S, Zamboni L. Differentiation of mouse ectopic germinal cells in intra- and perigonadal locations. J Exp Zool . 1985; 233 101-109
- 13 Upadhyay S, Zamboni L. Ectopic germ cells: natural model for the study of germ cell sexual differentiation. Proc Natl Acad Sci U S A . 1982; 79 6584-6588
- 14 Motta P M, Makabe S. Elimination of germ cells during differentiation of the human ovary: an electron microscope study. Eur J Obstet Gynecol Reprod Biol . 1986; 22 271-286
- 15 Palmer S J, Burgoyne P S. In situ analysis of fetal, prepubertal and adult XX-XY chimeric mouse testes: Sertoli cells are predominantly, but not exclusively, XY. Development . 1991; 112 265-268
- 16 Wilson E B. The sex chromosomes. Arch Mikrosk Anat Enwicklungsmech . 1911; 77 249-271
- 17 Ford C E, Miller O J, Polani P E. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner syndrome). Lancet . 1959; 1 711-713
- 18 Jacobs P A, Strong J A. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature . 1959; 183 302-303
- 19 Ferguson-Smith M A. X-Y chromosomal interchange in the aetiology of true hermaphroditism and of XX Klinefelter's syndrome. Lancet . 1966; 2 475-476
- 20 Page D C, Mosher R, Simpson E M. The sex-determining region of the human Y chromosome encodes a finger protein. Cell . 1987; 51 1091-1104
- 21 Singh L, Phillips C, Jones K W. The conserved nucleotide sequences of Bkm, which define Sxr in the mouse, are transcribed. Cell . 1984; 36 111-120
- 22 Wachtel S S, Ono S, Koo G C, Boyse E A. Possible role for H-Y antigen in the primary determination of sex. Nature . 1975; 257 235-236
- 23 Gubbay J, Collignon J, Koopman P. 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 . 1990; 346 245-250
- 24 Sinclair A H, Berta P, Palmer M S. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature . 1990; 346 240-244
- 25 Hanley N A, Hagan D M, Clement-Jones M. SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mech Dev . 2000; 91 403-407
- 26 Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature . 1990; 348 450-452
- 27 Berta P, Hawkins J R, Sinclair A H. Genetic evidence equating SRY and the testis-determining factor. Nature . 1990; 348 448-450
- 28 Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry Nature . 1991; 351 117-121
- 29 Dubin R A, Ostrer H. Sry is a transcriptional activator. Mol Endocrinol . 1994; 8 1182-1192
- 30 Giese K, Pagel J, Grosschedl R. Distinct DNA-binding properties of the high mobility group domain of murine and human SRY sex-determining factors. Proc Natl Acad Sci U S A . 1994; 91 3368-3372
- 31 Tucker P K, Lundrigan B L. Rapid evolution of the sex determining locus in old world mice and rats. Nature . 1993; 364 715-717
- 32 Whitfield L S, Lovell-Badge R, Goodfellow P N. Rapid sequence evolution of the mammalian sex-determining gene SRY Nature . 1993; 364 713-715
- 33 Bowles J, Cooper L, Berkman J, Koopman P. Sry requires a CAG repeat domain for male sex determination in Mus musculus Nat Genet . 1999; 22 405-408
- 34 Poulat F, Barbara P S, Desclozeau M. The human testis determining factor SRY binds a nuclear factor containing PDZ protein interaction domains. J Biol Chem . 1997; 272 7167-7172
- 35 Call K M, Glaser T, Ito C Y. Isolation and characterization of a zinc finger polypeptide gene XX at the human chromosome 11 Wilms' tumor locus. Cell . 1990; 60 509-520
- 36 Gessler M, Poustka A, Cavenee W, Neve R L, Orkin S H, Bruns G A. Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping. Nature . 1990; 343 774-778
- 37 Riccardi V M, Sujansky E, Smith A C, Francke U. Chromosomal imbalance in the aniridia-Wilms' tumor association: 11p interstitial deletion. Pediatrics . 1978; 61 604-610
- 38 Yunis J J, Ramsay N K. Familial occurrence of the aniridia-Wilms tumor syndrome with deletion 11p13-14.1 J Pediatr . 1980; 96 1027-1030
- 39 Hastie N D. Dominant negative mutations in the Wilms tumour (WT1) gene cause Denys-Drash syndrome: proof that a tumour-suppressor gene plays a crucial role in normal genitourinary development. Hum Mol Genet . 1992; 1 293-295
- 40 Schedl A, Hastie N. Multiple roles for the Wilms' tumour suppressor gene, WT1 in genitourinary development. Mol Cell Endocrinol . 1998; 140 65-69
- 41 Hanley N A, Ball S G, Clement-Jones M. Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination. Mech Dev . 1999; 87 175-180
- 42 Foster J W, Dominguez-Steglich M A, Guioll S. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature . 1994; 372 525-530
- 43 Hovmoller M L, Osuna A, Eklof O. Camptomelic dwarfism: a genetically determined mesenchymal disorder combined with sex reversal. Hereditas . 1977; 86 51-62
- 44 Tommerup N, Schempp W, Meinecke P. Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1 Nat Genet . 1993; 4 170-174
- 45 McDowall S, Argentaro A, Ranganathan S. Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem . 1999; 274 24023-24030
- 46 Huang B, Wang S, Ning Y, Lamb A N, Bartley J. Autosomal XX sex reversal caused by duplication of SOX9. Am J Med Genet . 1999; 87 349-353
- 47 Ikeda Y, Shen W H, Ingraham H A, Parker K L. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol . 1994; 8 654-662
- 48 Lala D S, Rice D A, Parker K L. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol . 1992; 6 1249-1258
- 49 Achermann J C, 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. Nat Genet . 1999; 22 125-126
- 50 McPherson E W, Clemens M M, Gibbons R J, Higgs D R. X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: a new kindred with severe genital anomalies and mild hematologic expression. Am J Med Genet . 1995; 55 302-306
- 51 Reardon W, Gibbons R J, Winter R M, Baraitser M. Male pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation (ATR-X) syndrome. Am J Med Genet . 1995; 55 285-287
- 52 Bardoni B, Zanaria E, Guioli S. A dosage sensitive locus at choromosome Xp21 is involved in male to female sex reversal. Nat Genet . 1994; 7 497-501
- 53 Bernstein R, Koo G C, Wachtel S S. Abnormality of the X chromosome in human 46,XY female siblings with dysgenic ovaries. Science . 1980; 207 768-769
- 54 Zanaria E, Muscatelli F, Bardoni B. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature . 1994; 372 635-641
- 55 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 . 1999; 99 409-419
- 56 De Santa Barbara P, Bonneaud N, Boizet B. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol . 1998; 18 6653-6665
- 57 Nachtigal M W, Hirokawa Y, Enyeart-VanHouten D L, Flanagan J N, Hammer G D, Ingraham H A. Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell . 1998; 93 445-454
- 58 Crawford P A, Dorn C, Sadovsky Y, Milbrandt J. Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol . 1998; 18 2949-2956
- 59 Ito M, Yu R, Jameson J L. DAX-1 inhibits SF-1-mediated transactivation via a carboxy- terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol . 1997; 17 1476-1483
- 60 Lalli E, Bardoni B, Zazopoulos E. A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol . 1997; 11 1950-1960
- 61 Kratzer P G, Chapman V M. X chromosome reactivation in oocytes of Mus caroli Proc Natl Acad Sci U S A . 1981; 78 3093-3097
- 62 Monk M, McLaren A. X-chromosome inactivation in foetal germ cells of the mouse. J Embryol Exp Morphol . 1981; 63 75-84
- 63 Simpson J L. Abnormal sexual differentiation in humans. Annu Rev Genet . 1982; 16 193-224
- 64 Therman E, Patau K. Abnormal X chromosomes in man: origin, behavior and effects. Humangenetik . 1974; 25 1-16
- 65 Krauss C M, Turksoy N, Atkins L, McLaughlin C, Brown L G, Page D C. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med . 1987; 317 125-131
- 66 Simpson J L. Genes, chromosomes, and reproductive failure. Fertil Steril . 1980; 33 107-116
- 67 Vainio S, Heikkila M, Kispert A, Chin N, McMahon A P. Female development in mammals is regulated by Wnt-4 signalling. Nature . 1999; 397 405-409
- 68 Hawkins J R, Taylor A, Goodfellow P N, Migeon C J, Smith K D, Berkovitz G D. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet . 1992; 51 979-984
- 69 Jager R J, Harley V R, Pfeiffer R A, Goodfellow P N, Scherer G. A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet . 1992; 90 350-355
- 70 Vilain E, McElreavey K, Jaubert F, Raymond J P, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet . 1992; 50 1008-1011
- 71 Crocker M, Cogill S B, Cortinho R. An unbalanced autosomal translocation (7;9) associated with feminization. Clin Genet . 1988; 34 70-73
- 72 Wilkie A O, Campbell F M, Daubeney P. Complete and partial XY sex reversal associated with terminal deletion of 10q: report of 2 cases and literature review. Am J Med Genet . 1993; 46 597-600
- 73 Ottolenghi C, Veitia R, Barbieri M, Fellous M, McElreavey K. The human doublesex-related gene, DMRT2, is homologous to a gene involved in somitogenesis and encodes a potential bicistronic transcript. Genomics . 2000; 64 179-186
- 74 Ottolenghi C, Veitia R, Quintana-Murci L. The region on 9p associated with 46,XY sex reversal contains several transcripts expressed in the urogenital system and a novel doublesex-related domain. Genomics . 2000; 64 170-178
- 75 Raymond C S, Parker E D, Kettlewell J R. A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Hum Mol Genet . 1999; 8 989-996
- 76 Raymond C S, Shamu C E, Shen M M. Evidence for evolutionary conservation of sex-determining genes. Nature . 1998; 391 691-695
- 77 Moniot B, Berta P, Scherer G, Sudbeck P, Poulat F. Male specific expression suggests role of DMRT1 in human sex determination. Mech Dev . 2000; 91 323-325
- 78 Raymond C S, Kettlewell J R, Hirsch B, Bardwell V J, Zarkower D. Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development. Dev Biol . 1999; 215 208-220
- 79 Miyamoto N, Yoshida M, Kuratani S, Matsuo I, Aizawa S. Defects of urogenital development in mice lacking Emx2 Development . 1997; 124 1653-1664
- 80 Katoh-Fukui Y, Tsuchiya R, Shiroishi T. Male-to-female sex reversal in M33 mutant mice. Nature . 1998; 393 688-692
- 81 Duggan D J, Bittner M, Chen Y, Meltzer P, Trent J M. Expression profiling using cDNA microarrays. Nat Genet . 1999; 21 10-14
- 82 Lipshutz R J, Fodor S P, Gingeras T R, Lockhart D J. High density synthetic oligonucleotide arrays. Nat Genet . 1999; 21 20-24
- 83 Grimmond S, Van Heteren N, Siggers P. Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggest a role in mammalian sexual development. Hum Mol Genet . 2000; 9 1553-1560
- 84 Cline T W, Meyer B J. Vive la difference: males vs. females in flies vs. worms. Annu Rev Genet . 1996; 30 637-702