Gender Identity

It may be your brain not your genitals that decides what sex you really are

[LOS ANGELES, CA] - Our brains could be hard-wired to be male or female long before we begin to grow testes or ovaries in the womb. This discovery might explain why some people feel trapped in a body that's the wrong sex, and could also lead to tests that reveal the 'brain sex' of babies born with ambiguous genitalia.

Till now, the orthodoxy among developmental biologists has been that embryos develop ovaries and become female unless a gene called SRY on the Y Chromosome is switched on. If this gene is active, it makes testes develop instead. This switch is seen as the key event in determining whether a baby is a girl or a boy. Only after the gonads form and flood the body with the appropriate hormones, the theory goes, is the sex of our minds and bodies determined.

But in a study of mice, a team at the University of California, Los Angeles, has now found that males and females show differences in the expression of no fewer than 50 genes well before SRY switches on.

"It's the first discovery of genes differentially expressed in the brain", says Eric Vilain, who led the UCLA team. "They may have an impact on the hard-wired development of the brain in terms of sexual differentiation independent of gonadal induction."

Vilain is presenting details of seven of the fifty genes to the annual meeting of the American Society of Human Genetics in Baltimore this week. Three of these genes are dominant in females and four are dominant in males. The next step for Vilain and his team will be to show that the genes in question really do influence brain sexuality - and not just in mice. This is likely to be a much tougher proposition than merely showing there are differences in expression.

But if the findings are confirmed, they could one day yield blood tests that allow doctors to establish the brain sex of babies born with genitalia that share the features of both sexes. At present doctors and parents have to guess which gender to assign for surgical 'correction'.

Robin Lovell Badge of the National Institute for Medical research in London, who discovered the SRY gene, is already looking at mice with a Y chromosome lacking the SRY gene, to see if their brains and behaviour are in any way male despite their lack of testes.

"The growing feeling is that there will be direct effects on the brain, anatomy, and behaviour due to X or Y-linked genes," says Lovell Badge.

"It's early days yet, but we're pretty sure there are effects on some aspects of aggression and reproductive behaviour independent of gonadal sex."

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Information about Eric Vilain
http://www.uclaaccess.ucla.edu/cfm/access_faculty.cfm?FacultyKey=430

Research Interest:

Genetics of Mammalian Sexual Development Sex determination orients development toward sexually dimorphic individuals, male or female. In mammals, male sex determination is triggered by a primary signal, encoded by the testis determining factor SRY, localized on the Y chromosome. Subsequently, a complex network of genes, most of them still unknown, is regulated and leads to male sexual differentiation. We have discovered new molecular and cellular mechanisms of sex determination during fetal development. In particular, we have provided strong evidence supporting SRY as the testis determining gene, and identified regulatory mechanisms of transcription of DAX1, another sex determining gene. We have also recently identified human WNT-4, a signalling molecule responsible, when duplicated, for XY sex reversal in mammals. A new concept is now emerging: normal sexual development is highly dependent on strict gene dosage at all major steps of the sex determination pathway.

My laboratory is exploring the genetics of development of the reproductive axis (hypothalamus-pituitary-gonads). Two complementary approaches are used: the analysis of patients with disorders of sexual development and the study of animal and cellular models. Specifically, we are searching for mutations in genes that are candidates for a role in developmental pathologies of the reproductive axis. We are also generating mouse models for disorders of sexual development. Finally, we are testing the hypothesis that there may be genetic influences on behavioral differences between males and females, in addition to the direct influence of sex steroids.

Recent Publications:

Jordan, BK; Jain, M; Natarajan, S; Frasier,SD; Vilain, E (2002)
Familial Mutation in the Testis-Determining Gene SRY Shared by an XY Female and Her Normal Father.
The Journal of Clinical Endocrinology & Metabolism 87 (7): 3428-3432.

Patel, M; Dorman, KS; Zhang, YH; Huang, BL; Arnold, AP; Sinsheimer, JS; Vilain, E; McCabe, ERB (2001)
Primate DAX1, SRY, and SOX9: evolutionary stratification of sex-determination pathway.
American Journal of Human Genetics 68: 275-280.

Jordan, BK; Mohammed, M; Ching, ST; Dlot, E; Chen, XN; Dewing, P; Swain, A; Rao, PN; Elejalde, BR; Vilain, E (2001)
Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans.
American Journal of Human Genetics 68: 1102-1109.

Dewing, P; Ching, ST; Zhang, YH; Huang, BL; Peirce, RM; McCabe, ER; Vilain, E (2000)
Midkine is expressed early in rat fetal adrenal development.
Molecular Genetics and Metabolism 71: 616-622.

Vilain E, LeMerrer M, Lecointre C, Desangles F, Kay MA, Maroteaux P, McCabe ERB (1999)
IMAGe: a new clinical association of Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita and Genital anomalies.
J. Clin. Endoc. Metab 84: 4335-4340.



Information about Robin Lovell Badge of the National Institute for Medical research in London, who discovered the SRY gene.

Dr. Robin Lovell-Badge
Contact Info:
http://www.nimr.mrc.ac.uk/devgen/publications.htm

Publications of research team:

http://www.nimr.mrc.ac.uk/devgen/publications.htm