In the mammalian embryo, both sexes are initially morphologically indistinguishable: specific hormones are required for sex-specific development. Müllerian inhibiting substance and testosterone secreted by the differentiating embryonic testes result in the loss of female (Müllerian) or promotion of male (Wolffian) reproductive duct development, respectively. The signalling molecule Wnt-4 is crucial for female sexual development. At birth, sexual development in males with a mutation in Wnt-4 appears to be normal; however, Wnt-4-mutant females are masculinized—the Müllerian duct is absent while the Wolffian duct continues to develop. Wnt-4 is initially required in both sexes for formation of the Müllerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis. Wnt-4 may also be required for maintenance of the female germ line. Thus, the establishment of sexual dimorphism is under the control of both local and systemic signals.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Burgoyne, P. S. Role of the mammalian Y chromosome in sex determination. Phil. Trans. R. Soc. Lond. B 322, 63–72 (1988).
Goodfellow, P. N. & Lovell-Badge, R. SRY and sex determination in mammals. Annu. Rev. Genet. 27, 71–92 (1993).
Sinclair, A. H. et al. Agene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 36, 240–244 (1990).
Gubbay, J. et al. Agene 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).
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).
Palmer, S. J. & Burgoyne, P. S. In situ analysis of fetal, prepubertal and adult XX–XY chimaeric mouse testes: Sertoli cells are predominantly, but not exclusively, XY. Development 112, 265–268 (1991).
Jost, A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog. Horm. Res. 8, 379–418 (1953).
Cate, R. L. et al. Isolation of the bovine and human genes for Müllerian-inhibiting substance and expression of the human gene in animal cells. Cell 45, 685–698 (1986).
Behringer, R. R., Finegold, M. J. & Cate, R. L. Müllerian-inhibiting substance function during mammalian sexual development. Cell 79, 415–425 (1994).
Bardoni, B. et al. Adosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet. 7, 497–501 (1994).
Zanaria, E. et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372, 635–641 (1994).
Muscatelli, F. et al. Mutations in the DAX-1 gene gives rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372, 672–676 (1994).
Swain, A., Narvaez, V., Burgoyne, P., Camerino, G. & Lovell-Badge, R. Dax1 antagonizes SRY action in mammalian sex determination. Nature 391, 761–767 (1998).
Cadigan, K. M. & Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286–3305 (1997).
Stark, K., Vainio, S., Vassileva, G. & McMahon, A. P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).
McLaren, A. Development of the mammalian gonad: the fate of the supporting cell lineage. BioEssays 13, 151–156 (1991).
Buehr, M., Gu, S. & McLaren, A. Mesonephric contribution to testis differentiation in the fetal mouse. Development 117, 273–281 (1993).
McLaren, A. Gonad development: assembling the mammalian testis. Curr. Biol. 8, 175–177 (1998).
Parr, B. A. & McMahon, A. P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998).
Miller, C. & Sassoon, D. A. Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development 125, 3201–3211 (1998).
Münsterberg, A. & Lovell-Badge, R. Expression of the mouse anti-Müllerian hormone gene suggests a role in both male and female sexual differentiation. Development 113, 613–624 (1991).
Bitgood, M. J., shen, L. & McMahon, A. P. Sertoli cell signaling by Desert hedgehog regulates the male germ line. Curr. Biol. 6, 298–304 (1996).
Morel, Y. et al. Structure-function relationships of 3β-hydroxysteroid dehydrogenase: contribution made by the molecular genetics of 3β-hydroxysteroid dehydrogenase deficiency. Steroids 62, 176–184 (1997).
Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are co-expressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995).
Kispert, A., Vainio, S., Shen, L., Rowitch, D. H. & McMahon, A. P. Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips. Development 122, 3627–3637 (1996).
Nordqvist, K. & Lovell-Badge, R. Setbacks on the road to sexual fulfillment. Nature Genet. 7, 7–9 (1994).
Andersson, S. et al. Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency. J. Clin. Endocrinol. Metab. 81, 130–136 (1996).
Nordqvist, K. & Tohonen, V. AmRNA differential display strategy for cloning genes expressed during mouse gonad development. Int. J. Dev. Biol. 41, 627–638 (1997).
Greco, T. L. & Payne, A. H. Ontogeny of expression of the genes for steroidogenic enzymes P450 side-chain cleavage, 3β-hydroxysteroid dehydrogenase, P450 17α-hydroxylase/C17–20 lyase and P450 aromatase in fetal mouse gonads. Endocrinology 135, 262–268 (1994).
Mustonen, M. V. J., Poutanen, M. H., Isomaa, V. V., Vihko, P. T. & Vihko, R. K. Cloning of mouse 17β-hydroxysteroid dehydrogenase type 2, and analyzing expression of the mRNAs for types 1, 2, 3, 4 and 5 in mouse embryos and adult tissues. Biochem. J. 325, 199–205 (1997).
Kent, J., Wheatley, S. C., Andrews, J. E., Sinclair, A. H. & Koopman, P. Amale-specific role for SOX9 in vertebrate sex determination. Development 122, 2813–2822 (1996).
McLaren, A. in Organization of the Early Vertebrate Embryo (eds Zagris, N., Duprat, A. M. & Durston, A. J.) 1–9 (Plenum, New York, (1995).
Enders, G. C. & May, J. J. I Developmentally regulated expression of a mouse germ cell nuclear antigen examined from embryonic day 11 to adult in male and female mice. Dev. Biol. 163, 331–340 (1994).
Lyet, L. et al. Ontogeny of reproductive abnormalities induced by deregulation of anti-Müllerian hormone expression in transgenic mice. Biol. Reprod. 52, 444–454 (1995).
Vigier, B., Watrin, F., Magre, S., Tran, D. & Josso, N. Purified bovine AMH induces a characteristic freemartin effect in fetal rat prospective ovaries exposed to it in vitro. Development 100, 43–55 (1987).
Behringer, R. R., Cate, R. L., Froelick, G. J., Palmiter, R. D. & Brinster, R. L. Abnormal sexual development in transgenic mice chronically expressing Müllerian inhibiting substance. Nature 345, 167–170 (1990).
Luo, X., Ikeda, Y. & Parker, K. L. Acell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490 (1994).
Sadovsky, Y. et al. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express p450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of glucocorticoids. Proc. Natl Acad. Sci. USA 92, 10939–10943 (1995).
Zamboni, L. & Upadhyay, S. Germ cell differentiation in mouse adrenal glands. J. Exp. Zool. 228, 178–193 (1983).
Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn. (Cold Spring Harbor Press, New York, (1994)).
Bishop, C. E., Boursot, P., Baron, B., Bonhomme, F. & Hatat, D. Most classical Mus musculus domesticus laboratory mouse strains carry a Mus musculus musuculus Y chromosome. Nature 315, 70–72 (1985).
We thank P. Donahue, R. Lovell-Badge, R. Vihko, H. Peltoketo, P. O'Shaughnessy, R.Maas, J. Smith, P. Gruss and G. Enders for supplying cDNAs used in hybridization analysis; G. Enders for supplying the GCNA-1 antibody; D. Rowitch for help in generating the Pax-2 transgenic mouse line; B.Klumpar for technical assistance; and A. McLaren, and R. Lovell-Badge for discussions. S.V. was supported by the academy of Finland, Finnish Cultural and Jusélius Foundations, and European Molecular Biology Organization; A.K. was the recipient of a long-term fellowship from Human Frontier Science Program Organization and Otto-Hahn Fellowship of the Max-Planck Society; and work in A.P.M.'s laboratory was funded by a grant from the NIDDK at the NIH.
About this article
Cite this article
Vainio, S., Heikkilä, M., Kispert, A. et al. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999). https://doi.org/10.1038/17068
Orphanet Journal of Rare Diseases (2021)
GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer
Scientific Reports (2021)
Copper and Selenium stimulates CYP19A1 expression in caprine ovarian granulosa cells: possible involvement of AKT and WNT signalling pathways
Molecular Biology Reports (2021)
Estrogen suppresses SOX9 and activates markers of female development in a human testis-derived cell line
BMC Molecular and Cell Biology (2020)