Identification of the Genes Regulated by Wnt-4, a Critical Signal for Commitment of the Ovary

Exp Cell Res. 2015 Mar 15;332(2):163-78. doi: 10.1016/j.yexcr.2015.01.010. Epub 2015 Jan 30.

Abstract

The indifferent mammalian embryonic gonad generates an ovary or testis, but the factors involved are still poorly known. The Wnt-4 signal represents one critical female determinant, since its absence leads to partial female-to-male sex reversal in mouse, but its signalling is as well implicated in the testis development. We used the Wnt-4 deficient mouse as a model to identify candidate gonadogenesis genes, and found that the Notum, Phlda2, Runx-1 and Msx1 genes are typical of the wild-type ovary and the Osr2, Dach2, Pitx2 and Tacr3 genes of the testis. Strikingly, the expression of these latter genes becomes reversed in the Wnt-4 knock-out ovary, suggesting a role in ovarian development. We identified the transcription factor Runx-1 as a Wnt-4 signalling target gene, since it is expressed in the ovary and is reduced upon Wnt-4 knock-out. Consistent with this, introduction of the Wnt-4 signal into early ovary cells ex vivo induces Runx-1 expression, while conversely Wnt-4 expression is down-regulated in the absence of Runx-1. We conclude that the Runx-1 gene can be a Wnt-4 signalling target, and that Runx-1 and Wnt-4 are mutually interdependent in their expression. The changes in gene expression due to the absence of Wnt-4 in gonads reflect the sexually dimorphic role of this signal and its complex gene network in mammalian gonad development.

Keywords: Female development; Germ line; Organogenesis; Ovary; Runx-1; Sex determination; Somatic cells; Testis; Wnt-4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cells, Cultured
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Female
  • Gene Expression
  • Gene Expression Regulation, Developmental*
  • Male
  • Mice, Knockout
  • Ovary / embryology
  • Ovary / metabolism*
  • Sex Determination Processes / genetics
  • Tissue Culture Techniques
  • Wnt Signaling Pathway
  • Wnt4 Protein / physiology*

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Runx1 protein, mouse
  • Wnt4 Protein
  • Wnt4 protein, mouse