Atlas of Wnt and R‐spondin gene expression in the developing male mouse lower urogenital tract

Abstract

Prostate development is influenced by β-catenin signaling, but it is unclear which β-catenin activators are involved, where they are synthesized, and whether their mRNA abundance is influenced by androgens. We identified WNT/β-catenin-responsive β-galactosidase activity in the lower urogenital tract (LUT) of transgenic reporter mice, but β-galactosidase activity differed among the four mouse strains we examined. We used in situ hybridization to compare patterns of Wnts, r-spondins (Rspos, co-activators of β-catenin signaling), β-catenin-responsive mRNAs, and an androgen receptor-responsive mRNA in wild type fetal male, fetal female, and neonatal male LUT. Most Wnt and Rspo mRNAs were present in LUT during prostate development. Sexually dimorphic expression patterns were observed for WNT/β-catenin-responsive genes, and for Wnt2b, Wnt4, Wnt7a, Wnt9b, Wnt10b, Wnt11, Wnt16, and Rspo3 mRNAs. These results reveal sexual differences in WNT/β-catenin signaling in fetal LUT, supporting the idea that this pathway may be directly or indirectly responsive to androgens during prostate ductal development.

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

“…In particular, several Wnt ligands are upregulated during the period of prostatic bud formation Pritchard et al, 2009;Zhang et al, 2006). Furthermore, analyses using sensitive transgene reporters have shown that Wnt signaling activity is present in the mouse UGM prior to prostate budding and subsequently in both the mesenchyme and ductal tips during outgrowth (Kruithof-de Julio et al, 2013;Mehta et al, 2011). Consistent with these findings, downstream targets of canonical Wnt signaling such as Lef1 are expressed in epithelial cells of prostate ductal tips (Francis et al, 2013;Mehta et al, 2013;Wu et al, 2011).…”

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

“…Yet in developing mouse prostate, Wif1 is expressed in UGM and UGE and overlaps WNT/␤-cateninresponsive Axin2 and Lef1 (lymphoid enhancer binding factor 1) expression (14,15,19). Coexpression of Wif1 with abundant WNT/␤-catenin-responsive mRNA expression would not be predicted if WIF1 functioned as a strong WNT/␤-catenin inhibitor in control UGS.…”

“…Coexpression of Wif1 with abundant WNT/␤-catenin-responsive mRNA expression would not be predicted if WIF1 functioned as a strong WNT/␤-catenin inhibitor in control UGS. We tested whether prostatic bud-enhancing concentrations of exogenous WIF1 protein visibly altered the pattern of WNT/␤-catenin-responsive Axin2 and Lef1 mRNA within and immediately surrounding prostatic bud tips in which both mRNAs were detected previously (19). E14.5 male UGSs were grown for 4 d in UGS organ culture media containing DHT and graded recombinant WIF1 protein concentrations.…”

“…Immunofluorescent staining of ISH-stained, frozen, paraffin, and vibrating microtome sections was performed as described previously (19,26 …”

“…The WNT pathway has been identified as a major androgen-responsive pathway in developing UGS and many Wnts are more abundant in male compared with female mouse UGS (14,15,19). Several WNT antagonists are also present during prostate development, including but not limited to WNT inhibitory factor 1 (Wif1) and secreted frizzled related proteins (Sfrps) 1 and -2 (14,15,20).…”