Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development

Abstract

Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5␣-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/␤-catenin-responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation. (Endocrinology 153: 6091-6103, 2012) A ndrogens initiate prostatic bud formation from the urogenital sinus (UGS) and stimulate prostatic bud elongation, ductal branching morphogenesis, and differentiation of mature prostatic ductal epithelium (1, 2). During fetal prostate development, androgens activate androgen receptors (ARs) in UGS mesenchyme (UGM) to induce prostatic bud formation in UGS epithelium (UGE) (1, 3-5). The developing prostate has therefore been used as a model to assess the role of androgens in mesenchymal/epithelial interactions. A longstanding question in the prostate development field is how ARs in UGM communicate with UGE to establish the pattern and quantity of prostatic buds that will form. Continued investigation is expected to shed light on how the developing prostate microenvironment influences prostate epithelial cell fate. It may also elucidate how adult prostate stromal ARs reactivate developmental signaling pathways to cause inappropriate proliferative growth during prostate disease (6 -13).Numerous gene expression profiling studies have been conducted to identify androgen-responsive mRNAs in fe-

RET-mediated glial cell line derived neurotrophic factor signaling inhibits mouse prostate development

“…7). This mechanism is consistent with previous reports of paracrine signaling for secreted ligands of the WNT (Allgeier et al, 2008;Huang et al, 2009;Joesting et al, 2008;Keil et al, 2012), FGF (Alarid et al, 1994;Donjacour et al, 2003;Sugimura et al, 1996;Thomson and Cunha, 1999) and TGFβ (Cancilla et al, 2001;Cook Fig. 6.…”

“…Outgrowth of the PrE is dictated by time-specific and cell-specific expression of morphogenetic genes (Prins and Putz, 2008;Thomson and Marker, 2006), including secreted signaling ligands of the hedgehog (Berman et al, 2004;Doles et al, 2006;Freestone et al, 2003;Lamm et al, 2002;Podlasek et al, 1999;Pu et al, 2004;Wang et al, 2003), Wnt (Allgeier et al, 2008;Huang et al, 2009;Joesting et al, 2008;Keil et al, 2012), FGF (Alarid et al, 1994;Donjacour et al, 2003;Sugimura et al, 1996;Thomson and Cunha, 1999) and TGFβ (Cancilla et al, 2001;Cook et al, 2007;Grishina et al, 2005;Itoh et al, 1998;Lamm et al, 2001;Tanji et al, 1994;Tomlinson et al, 2004) gene super-families. These morphogens are thought to communicate autocrine and paracrine signals through their cognate receptors and downstream signaling pathways.…”

Prostate organogenesis: tissue induction, hormonal regulation and cell type specification

“…However, there is currently no direct evidence that Wnt ligands are androgen regulated, and thus they do not currently fulfill all of the criteria for being considered andromedins. Interestingly, the Wnt inhibitor Wif1 is expressed at higher levels in the UGM of males and is androgen regulated, but Wif1 null mutants lack a prostate phenotype (Keil et al, 2012b), and consequently the role of Wif1 in prostate formation remains unclear.…”

Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development

“…ARs are especially abundant in a subpopulation of mouse UGS mesenchymal cells known as lamina propria mesenchyme. Radiolabeled testosterone binding in this cell population is detectable beginning around 15 dpc (11) and coincides with onset of androgen responsive steroid 5 alpha reductase type 2 ( Srd5a2 ) and Wnt inhibitor factor 1 ( Wif1 ) mRNA expression (12, 13). However, mouse prostate development lags behind the onset of gonadal testosterone synthesis and AR binding by several days, a feature shared by other mammalian species (14).…”