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Proc Natl Acad Sci U S A. Apr 15, 1993; 90(8): 3368–3372.
PMCID: PMC46301

A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development.

Abstract

The mammalian Y chromosome carries the SRY gene, which determines testis formation. Here we review data on individuals who are XX but exhibit male characteristics: some have SRY; others do not. We have analyzed three families containing more than one such individual and show that these individuals lack SRY. Pedigree analysis leads to the hypothesis that they carry recessive mutations (in a gene termed Z) that allow expression of male characteristics. We propose that wild-type Z product is a negative regulator of male sex determination and is functional in wild-type females. In males, SRY product represses or otherwise negatively regulates Z and thereby allows male sex determination. This hypothesis can also explain other types of sex reversal in mammals, in particular, XY females containing SRY. Some of these individuals may have mutations at the Z locus rendering them insensitive to SRY. Recessive mutations (such as the polled mutation of goats) leading to sex reversal are known in a variety of animals and might be used to map and ultimately clone the human Z gene.

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  • Burgoyne PS. Role of mammalian Y chromosome in sex determination. Philos Trans R Soc Lond B Biol Sci. 1988 Dec 1;322(1208):63–72. [PubMed]
  • Sex determination in mouse and man. Philos Trans R Soc Lond B Biol Sci. 1988 Dec 1;322(1208):1–157. [PubMed]
  • Goodfellow PN, Darling SM. Genetics of sex determination in man and mouse. Development. 1988 Feb;102(2):251–258. [PubMed]
  • Eicher EM, Washburn LL. Genetic control of primary sex determination in mice. Annu Rev Genet. 1986;20:327–360. [PubMed]
  • Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990 Jul 19;346(6281):240–244. [PubMed]
  • Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448–450. [PubMed]
  • Jäger RJ, Anvret M, Hall K, Scherer G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature. 1990 Nov 29;348(6300):452–454. [PubMed]
  • Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471–474. [PubMed]
  • McElreavey KD, Vilain E, Boucekkine C, Vidaud M, Jaubert F, Richaud F, Fellous M. XY sex reversal associated with a nonsense mutation in SRY. Genomics. 1992 Jul;13(3):838–840. [PubMed]
  • McElreavy K, Vilain E, Abbas N, Costa JM, Souleyreau N, Kucheria K, Boucekkine C, Thibaud E, Brauner R, Flamant F, et al. XY sex reversal associated with a deletion 5' to the SRY "HMG box" in the testis-determining region. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11016–11020. [PMC free article] [PubMed]
  • Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry. Nature. 1991 May 9;351(6322):117–121. [PubMed]
  • Hodgkin J. Sex determination compared in Drosophila and Caenorhabditis. Nature. 1990 Apr 19;344(6268):721–728. [PubMed]
  • Nasrin N, Buggs C, Kong XF, Carnazza J, Goebl M, Alexander-Bridges M. DNA-binding properties of the product of the testis-determining gene and a related protein. Nature. 1991 Nov 28;354(6351):317–320. [PubMed]
  • Harley VR, Jackson DI, Hextall PJ, Hawkins JR, Berkovitz GD, Sockanathan S, Lovell-Badge R, Goodfellow PN. DNA binding activity of recombinant SRY from normal males and XY females. Science. 1992 Jan 24;255(5043):453–456. [PubMed]
  • Giese K, Cox J, Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell. 1992 Apr 3;69(1):185–195. [PubMed]
  • de la Chapelle A. The etiology of maleness in XX men. Hum Genet. 1981;58(1):105–116. [PubMed]
  • Seboun E, Leroy P, Casanova M, Magenis E, Boucekkine C, Disteche C, Bishop C, Fellous M. A molecular approach to the study of the human Y chromosome and anomalies of sex determination in man. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):237–248. [PubMed]
  • Guellaen G, Casanova M, Bishop C, Geldwerth D, Andre G, Fellous M, Weissenbach J. Human XX males with Y single-copy DNA fragments. Nature. 1984 Jan 12;307(5947):172–173. [PubMed]
  • Abbas NE, Toublanc JE, Boucekkine C, Toublanc M, Affara NA, Job JC, Fellous M. A possible common origin of "Y-negative" human XX males and XX true hermaphrodites. Hum Genet. 1990 Mar;84(4):356–360. [PubMed]
  • McElreavey K, Rappaport R, Vilain E, Abbas N, Richaud F, Lortat-Jacob S, Berger R, Le Coniat M, Boucekkine C, Kucheria K, et al. A minority of 46,XX true hermaphrodites are positive for the Y-DNA sequence including SRY. Hum Genet. 1992 Sep-Oct;90(1-2):121–125. [PubMed]
  • Affara NA, Florentin L, Morrison N, Kwok K, Mitchell M, Cook A, Jamieson D, Glasgow L, Meredith L, Boyd E, et al. Regional assignment of Y-linked DNA probes by deletion mapping and their homology with X-chromosome and autosomal sequences. Nucleic Acids Res. 1986 Jul 11;14(13):5353–5373. [PMC free article] [PubMed]
  • Page DC, Mosher R, Simpson EM, Fisher EM, Mardon G, Pollack J, McGillivray B, de la Chapelle A, Brown LG. The sex-determining region of the human Y chromosome encodes a finger protein. Cell. 1987 Dec 24;51(6):1091–1104. [PubMed]
  • Palmer MS, Sinclair AH, Berta P, Ellis NA, Goodfellow PN, Abbas NE, Fellous M. Genetic evidence that ZFY is not the testis-determining factor. Nature. 1989 Dec 21;342(6252):937–939. [PubMed]
  • Ellis NA, Goodfellow PJ, Pym B, Smith M, Palmer M, Frischauf AM, Goodfellow PN. The pseudoautosomal boundary in man is defined by an Alu repeat sequence inserted on the Y chromosome. Nature. 1989 Jan 5;337(6202):81–84. [PubMed]
  • Vergnaud G, Page DC, Simmler MC, Brown L, Rouyer F, Noel B, Botstein D, de la Chapelle A, Weissenbach J. A deletion map of the human Y chromosome based on DNA hybridization. Am J Hum Genet. 1986 Feb;38(2):109–124. [PMC free article] [PubMed]
  • Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet. 1992 May;50(5):1008–1011. [PMC free article] [PubMed]
  • Armendares S, Salamanca F, Cantú JM, Del Castillo V, Nava S, Dominguez-de-la-Piedra E, Cortés-Gallegos V, Gallegos A, Cervantes C, Parra A. Familial true hermaphrodism in three siblings: clinical, cytogenetic, histological and hormonal studies. Humangenetik. 1975 Sep 10;29(2):99–109. [PubMed]
  • de la Chapelle A, Tippett PA, Wetterstrand G, Page D. Genetic evidence of X-Y interchange in a human XX male. Nature. 1984 Jan 12;307(5947):170–171. [PubMed]
  • de la Chapelle A. The Y-chromosomal and autosomal testis-determining genes. Development. 1987;101 (Suppl):33–38. [PubMed]
  • Selden JR, Wachtel SS, Koo GC, Haskins ME, Patterson DF. Genetic basis of XX male syndrome and XX true hermaphroditism: evidence in the dog. Science. 1978 Aug 18;201(4356):644–646. [PubMed]
  • Wachtel SS, Basrur P, Koo GC. Recessive male-determining genes. Cell. 1978 Sep;15(1):279–281. [PubMed]
  • Sittmann K, Breeuwsma AJ, te Brake JH. On the inheritance of intersexuality in swine. Can J Genet Cytol. 1980;22(4):507–527. [PubMed]
  • Cribiu EP, Chaffaux S. L'intersexualité chez les mammifères domestiques. Reprod Nutr Dev. 1990;Suppl 1:51s–61s. [PubMed]
  • Hamerton JL, Dickson JM, Pollard CE, Grieves SA, Short RV. Genetic intersexuality in goats. J Reprod Fertil Suppl. 1969 May;7(Suppl):25–51. [PubMed]
  • Travis A, Amsterdam A, Belanger C, Grosschedl R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991 May;5(5):880–894. [PubMed]
  • Castrop J, van Norren K, Clevers H. A gene family of HMG-box transcription factors with homology to TCF-1. Nucleic Acids Res. 1992 Feb 11;20(3):611–611. [PMC free article] [PubMed]
  • Skordis NA, Stetka DG, MacGillivray MH, Greenfield SP. Familial 46,XX males coexisting with familial 46,XX true hermaphrodites in same pedigree. J Pediatr. 1987 Feb;110(2):244–248. [PubMed]
  • JACOB F, MONOD J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol. 1961 Jun;3:318–356. [PubMed]
  • Washburn LL, Eicher EM. Normal testis determination in the mouse depends on genetic interaction of a locus on chromosome 17 and the Y chromosome. Genetics. 1989 Sep;123(1):173–179. [PMC free article] [PubMed]
  • Mitchell AP, Herskowitz I. Activation of meiosis and sporulation by repression of the RME1 product in yeast. Nature. 319(6056):738–742. [PubMed]
  • Banuett F. Identification of genes governing filamentous growth and tumor induction by the plant pathogen Ustilago maydis. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3922–3926. [PMC free article] [PubMed]
  • Hodgkin J. Sex determination compared in Drosophila and Caenorhabditis. Nature. 1990 Apr 19;344(6268):721–728. [PubMed]

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