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Female development in mammals is regulated by Wnt-4 signalling


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.

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Figure 1: Expression of the Wnt-4 gene during gonad development.
Figure 2: Sex reversal in the reproductive system of Wnt-4-mutant females.
Figure 3: Sex-independent regulation of Müllerian duct formation by Wnt-4.
Figure 4: Ectopic expression of Leydig cell markers, 3β-HSD and 17α-hydroxylase genes, in the gonad of Wnt-4-mutant females.
Figure 5: Oocyte development is dependent on Wnt-4.


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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.

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Correspondence to Andrew P. McMahon.

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Vainio, S., Heikkilä, M., Kispert, A. et al. Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409 (1999).

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