Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling

• Hedgehog signaling is growth promoting pre-natally and growth inhibitory post-natally during prostate development.
• There is a discordant regulation of a subset of hedgehog target genes in the pre and post natal prostate.
• Cellular microenvironment regulates stage-specific growth effects.

Published studies of Hh (Hedgehog) signaling in the developing prostate have reported varying and discrepant effects on epithelial proliferation, ductal morphogenesis and growth. We report here that these differing observations accrue from stage-specific effects of Hh signaling in the developing prostate. Using in vitro organ cultures of the E16 UGS and P1 prostate, we show that ectopic Hh pathway activation stimulates epithelial proliferation prenatally, but inhibits epithelial proliferation postnatally. Extrapolating from previously published observations that Hh target gene expression is altered in the reactive stroma of prostate cancer, we examined and found discordant regulation of a subset of target genes by Hh signaling in the prenatal and postnatal prostate. Cell based studies and recombination assays show that these changes are not simply attributable to the age of the mesenchyme or the epithelium, but more likely reflect a complex regulation by the cellular microenvironment. To determine the in vivo relevance of these observations, we examined the effect of transgenic activation of Hh signaling on epithelial proliferation in the prenatal and postnatal prostate and confirmed the operation of stage-specific effects. These observations demonstrate stage-specific differences in the effect of Hh signaling on epithelial proliferation in the developing prostate and suggest that these are a product of complex interactions determined by the cellular microenvironment.