TY - JOUR
T1 - Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans
AU - Jordan, Brian K.
AU - Mohammed, Mansoor
AU - Ching, Saunders T.
AU - Délot, Emmanuèle
AU - Chen, Xiao Ning
AU - Dewing, Phoebe
AU - Swain, Amanda
AU - Rao, P. Nagesh
AU - Elejalde, B. Rafael
AU - Vilain, Eric
N1 - Funding Information:
We thank A. McMahon for the Wnt-4 construct, D. H. Cohn for the radiation-hybrid panel, and E. R. B. McCabe for discussion and critical comments. We are also grateful to Susan and Eric Smidt for their generous gift. This work was supported by grants from the National Institutes of Health (to E.V., P.D., and X.-N.C.) and from the Medical Investigation of Neurodevelopmental Disorders Institute (to B.K.J.).
PY - 2001
Y1 - 2001
N2 - Wnt-4, a member of the Wnt family of locally acting secreted growth factors, is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization of XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a strong candidate gene for sex-reversal phenotypes in humans. In this article, we show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax1, a gene known to antagonize the testis-determining factor, Sry. Furthermore, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WNT-4, a novel sex-determining gene, and DAX1 play a concerted role in both the control of female development and the prevention of testes formation. These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway.
AB - Wnt-4, a member of the Wnt family of locally acting secreted growth factors, is the first signaling molecule shown to influence the sex-determination cascade. In mice, a targeted deletion of Wnt-4 causes the masculinization of XX pups. Therefore, WNT-4, the human homologue of murine Wnt-4, is a strong candidate gene for sex-reversal phenotypes in humans. In this article, we show that, in testicular Sertoli and Leydig cells, Wnt-4 up-regulates Dax1, a gene known to antagonize the testis-determining factor, Sry. Furthermore, we elucidate a possible mechanism for human XY sex reversal associated with a 1p31-p35 duplication including WNT-4. Overexpression of WNT-4 leads to up-regulation of DAX1, which results in an XY female phenotype. Thus, WNT-4, a novel sex-determining gene, and DAX1 play a concerted role in both the control of female development and the prevention of testes formation. These observations suggest that mammalian sex determination is sensitive to dosage, at multiple steps in its pathway.
UR - http://www.scopus.com/inward/record.url?scp=0035002512&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035002512&partnerID=8YFLogxK
U2 - 10.1086/320125
DO - 10.1086/320125
M3 - Article
C2 - 11283799
AN - SCOPUS:0035002512
SN - 0002-9297
VL - 68
SP - 1102
EP - 1109
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -