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Female development in mammals is regulated by Wnt-4 signalling

Abstract

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.

References

  1. 1

    Burgoyne, P. S. Role of the mammalian Y chromosome in sex determination. Phil. Trans. R. Soc. Lond. B 322, 63–72 (1988).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Goodfellow, P. N. & Lovell-Badge, R. SRY and sex determination in mammals. Annu. Rev. Genet. 27, 71–92 (1993).

    CAS  Article  Google Scholar 

  3. 3

    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).

    ADS  Article  Google Scholar 

  4. 4

    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).

    ADS  CAS  Article  Google Scholar 

  5. 5

    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).

    ADS  CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    Jost, A. Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Prog. Horm. Res. 8, 379–418 (1953).

    Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    Behringer, R. R., Finegold, M. J. & Cate, R. L. Müllerian-inhibiting substance function during mammalian sexual development. Cell 79, 415–425 (1994).

    CAS  Article  Google Scholar 

  10. 10

    Bardoni, B. et al. Adosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet. 7, 497–501 (1994).

    CAS  Article  Google Scholar 

  11. 11

    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).

    ADS  CAS  Article  Google Scholar 

  12. 12

    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).

    ADS  CAS  Article  Google Scholar 

  13. 13

    Swain, A., Narvaez, V., Burgoyne, P., Camerino, G. & Lovell-Badge, R. Dax1 antagonizes SRY action in mammalian sex determination. Nature 391, 761–767 (1998).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Cadigan, K. M. & Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286–3305 (1997).

    CAS  Article  Google Scholar 

  15. 15

    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).

    ADS  CAS  Article  Google Scholar 

  16. 16

    McLaren, A. Development of the mammalian gonad: the fate of the supporting cell lineage. BioEssays 13, 151–156 (1991).

    CAS  Article  Google Scholar 

  17. 17

    Buehr, M., Gu, S. & McLaren, A. Mesonephric contribution to testis differentiation in the fetal mouse. Development 117, 273–281 (1993).

    CAS  PubMed  Google Scholar 

  18. 18

    McLaren, A. Gonad development: assembling the mammalian testis. Curr. Biol. 8, 175–177 (1998).

    Article  Google Scholar 

  19. 19

    Parr, B. A. & McMahon, A. P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395, 707–710 (1998).

    ADS  CAS  Article  Google Scholar 

  20. 20

    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).

    CAS  PubMed  Google Scholar 

  21. 21

    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).

    PubMed  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  Article  Google Scholar 

  25. 25

    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).

    CAS  PubMed  Google Scholar 

  26. 26

    Nordqvist, K. & Lovell-Badge, R. Setbacks on the road to sexual fulfillment. Nature Genet. 7, 7–9 (1994).

    CAS  Article  Google Scholar 

  27. 27

    Andersson, S. et al. Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency. J. Clin. Endocrinol. Metab. 81, 130–136 (1996).

    CAS  PubMed  Google Scholar 

  28. 28

    Nordqvist, K. & Tohonen, V. AmRNA differential display strategy for cloning genes expressed during mouse gonad development. Int. J. Dev. Biol. 41, 627–638 (1997).

    CAS  PubMed  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  PubMed  Google Scholar 

  32. 32

    McLaren, A. in Organization of the Early Vertebrate Embryo (eds Zagris, N., Duprat, A. M. & Durston, A. J.) 1–9 (Plenum, New York, (1995).

    Book  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    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).

    CAS  Article  Google Scholar 

  35. 35

    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).

    CAS  PubMed  Google Scholar 

  36. 36

    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).

    ADS  CAS  Article  Google Scholar 

  37. 37

    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).

    CAS  Article  Google Scholar 

  38. 38

    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).

    ADS  CAS  Article  Google Scholar 

  39. 39

    Zamboni, L. & Upadhyay, S. Germ cell differentiation in mouse adrenal glands. J. Exp. Zool. 228, 178–193 (1983).

    Article  Google Scholar 

  40. 40

    Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn. (Cold Spring Harbor Press, New York, (1994)).

    Google Scholar 

  41. 41

    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).

    ADS  CAS  Article  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/17068

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