WNT2 is necessary for normal prostate gland cyto-differentiation and modulates prostate growth in an FGF10 dependent manner

Wnt proteins are highly conserved secreted morphogens that function in organ development across species. This study investigates the role(s) of Wnt2 during prostate gland development. Wnt2 mRNA ontogeny in the rat ventral prostate rapidly declines in expression from peak value at post-natal day (pnd) 1 to nadir levels sustained through adulthood. Wnt2 mRNA is expressed in prostate mesenchymal cells and Wnt2 protein localizes to both mesenchymal and epithelial cells. Sustained expression of Wnt2 by adenoviral expression during rat postnatal prostate gland development resulted in significant reduction in gland size confirming its necessary decline to permit normal development. Wnt2 overexpression in a murine embryonic urogenital sinus mesenchyme cell line, UGSM2 revealed Wnt2 modulated several growth factors including significant down-regulation of Fgf10, an essential stimulator of normal prostate gland branching morphogenesis. Growth inhibitory effects of Wnt2 were reversed by exogenous Fgf10 addition to developing rat ventral prostates. Renal grafts of Wnt2-/- male urogenital sinus revealed that Wnt2-/- grafts had a disruption in normal lateral polarity, disruption in cell to cell adhesion, and a reduction in the differentiated luminal cell marker, cytokeratin 8/18. Our results demonstrate that the growth inhibiting effects of sustained Wnt2 during prostate development are mediated, in part, by reduction in Fgf10 expression by mesenchymal cells and Wnt2 plays a role in normal prostate luminal cell differentiation and cell to cell integrity. These findings add to the body of work that highlights the unique roles of individual Wnts during prostate development and suggest that their deregulation may be implicated in prostate pathology