Sonic Hedgehog-patched Gli Signaling in the Developing Rat Prostate Gland: Lobe-specific Suppression by Neonatal Estrogens Reduces Ductal Growth and Branching

While prostate gland development is dependent on androgens, other hormones including retinoids and estrogens can influence this process. Brief exposure to high-dose estrogen during the neonatal period in rats leads to permanent, lobe-specific aberrations in the prostate gland, a phenomenon referred to as developmental estrogenization. We have previously shown that this response is mediated through alterations in steroid receptor expression; however, further downstream mechanisms remain unclear. Herein, we examined Sonic hedgehog (Shh)-patched (ptc)-gli in the developing rat prostate gland, its role in branching morphogenesis, and the effects of neonatal estrogens on its expression and localization to determine whether a disturbance in this signaling pathway is involved in mediating the estrogenized phenotype. Shh was expressed in epithelial cells at the distal tips of elongating ducts in discreet, heterogeneous foci, while ptc and gli1-3 were expressed in the adjacent mesenchymal cells in the developing gland. The addition of Shh protein to cultured neonatal prostates reduced ductal growth and branching, decreased Fgf10 transcript, and increased Bmp4 expression in the adjacent mesenchyme. Shh-induced growth suppression was reversed by exogenous Fgf10, but not noggin, indicating that Fgf10 suppression is the proximate cause of the growth inhibition. A model is proposed to show how highly localized Shh expression along with regulation of downstream morphogens participates in dichotomous branching during prostate morphogenesis. Neonatal exposure to high-dose estradiol suppressed Shh, ptc, gli1, and gli3 expressions and concomitantly blocked ductal branching in the dorsal and lateral prostate lobes specifically. In contrast, ventral lobe branching and Shh-ptc-gli expression were minimally affected by estrogen exposure. Organ culture studies with lateral prostates confirmed that estradiol suppressed Shh-ptc-gli expression directly at the prostatic level. Taken together, the present findings indicate that lobe-specific decreases in Shh-ptc-gli expression are involved in mediating estradiol-induced suppression of dorsal and lateral lobe ductal growth and branching during prostate morphogenesis.