Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad

Abstract

The signalling molecule WNT4 has been associated with sex reversal phenotypes in mammals. Here we show that the role of WNT4 in gonad development is to pattern the sex-specific vasculature and to regulate steroidogenic cell recruitment. Vascular formation and steroid production in the mammalian gonad occur in a sex-specific manner. During testis development, endothelial cells migrate from the mesonephros into the gonad to form a coelomic blood vessel. Leydig cells differentiate and produce steroid hormones a day later. Neither of these events occurs in the XX gonad. We show that WNT4 represses mesonephric endothelial and steroidogenic cell migration in the XX gonad, preventing the formation of a male-specific coelomic blood vessel and the production of steroids. In the XY gonad, Wnt4 expression is downregulated after sex determination. Transgenic misexpression of Wnt4 in the embryonic testis did not inhibit coelomic vessel formation but vascular pattern was affected. Leydig cell differentiation was not affected in these transgenic animals and our data implies that Wnt4 does not regulate steroidogenic cell differentiation but represses the migration of steroidogenic adrenal precursors into the gonad. These studies provide a model for understanding how the same signalling molecule can act on two different cell types to coordinate sex development.

Presumptive pre‐sertoli cells express genes involved in cell proliferation and cell signalling during a critical window in early testis differentiation

“…Within the kidney, Wnt6 plays a role in tubulogenesis (Itäranta et al, 2002), and can have both redundant and antagonistic functions with Wnt4 (Itä ranta et al, 2002). Within the developing ovary, the proper development of the Mü llerian ducts and the repression of testosterone production depend upon Wnt4 expression (Vainio et al, 1999;Jeays-Ward et al, 2003). In our microarray study Wnt6 is expressed at a higher level in pre-Sertoli cells compared to the XX genital ridge cells.…”

R-spondin1, WNT4, and the CTNNB1 signaling pathway: strict control over ovarian differentiation

“…In mice, Wnt4 has been shown to be important for multiple morphogenetic processes, including formation of the kidney, adrenal and mammary glands and the reproductive tract where it regulates endothelial and steroidogenic cell migration (Jeays-Ward et al 2003), sex determination (Kim et al 2006), and female development (Vainio et al 1999).…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…Targeted deletion of Wnt-2 in mice leads to a defective fetal capillary network in the placenta (23). Wnt-4 mutant mice exhibit defective coelomic blood vessel formation in the male gonad (24). Replacement of the first exon of Wnt-7b with the lacZ gene leads to severe pulmonary hemorrhage derived from defective vascular smooth muscle cell integrity in mice (25).…”