Sonic hedgehog regulates prostatic growth and epithelial differentiation

Abstract

The Sonic hedgehog (SHH)-signalling pathway mediates epithelial-mesenchymal interactions in several tissues during development and disease, and we have investigated its role in rat ventral prostate (VP) development. We have demonstrated that Shh and Ptc expression correlates with growth and development of the prostate and that their expression is not regulated by androgens in the VP. Prostatic budding was induced in response to testosterone in Shh null mouse urogenital sinus (UGS) explants grown in vitro and in rat UGS explants cultured with cyclopamine, suggesting that SHH-signalling is not critical for prostatic induction. SHH-signalling was disrupted at later stages of VP development (in vitro), resulting in a reduction in organ size, an increase in ductal tip number, and reduced proliferation of ductal tip epithelia. The addition of recombinant SHH to VPs grown in vitro caused a decrease in ductal tip number and expansion of the mesenchyme. In the presence of testosterone, inhibition of SHH-signalling accelerated the canalisation of prostatic epithelial ducts and resulted in ducts that showed morphological similarities to cribiform prostatic intraepithelial neoplasia (PIN). The epithelia of these ducts also demonstrated precocious and aberrant differentiation, when examined by immunohistochemistry for p63 and cytokeratin 14. In conclusion, we show that SHH-signalling is not essential for prostatic induction, but is important for prostatic growth, branching, and proliferation, and that androgen-stimulated growth in the absence of signalling from the SHH pathway results in aberrant epithelial differentiation.

p63 Overexpression Induces the Expression of Sonic Hedgehog

“…Shh has been shown to be essential for the development of brain, limbs, prostate, teeth, and hair follicles (21)(22)(23). If p63 is indeed involved in the expression of Shh, then a reduction in the levels of Shh would be expected in cells lacking p63.…”

“…Sonic Hedgehog (Shh) is a morphogen that is essential for the development of the brain, limbs, prostate, hair follicles, and teeth (21)(22)(23). The Shh signaling pathway controls the proliferation of precursor cells with stem cell properties (24).…”

“…The Shh signaling pathway controls the proliferation of precursor cells with stem cell properties (24). Shh is involved in ductal morphogenesis, regeneration of prostate epithelium, and prostate cancer progression (23). Although Shh is an important regulator of development, the regulatory mechanisms responsible for Shh expression remain unclear.…”

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

“…Embryonic endoderm gives rise to the bladder urothelium while the connective tissues and smooth muscle of the developing bladder are derived from the peri-cloacal mesenchyme (Haraguchi et al, 2007;Brenner-Anantharam et al, 2007). Genetic studies indicate the homeobox genes play an important role in determining the global patterning of the urogenital system (Satokata et al, 1995;Sciavolino et al, 1997;Warot et al, 1997;Goodman and Scambler, 2001;de Santa and Roberts, 2002;Troy et al, 2003), while key signaling molecules like sonic hedgehog and wnts have been implicated in determining the regional patterning within specific urogenital organs (Perriton et al, 2002;Freestone et al, 2003;Mericskay et al, 2004). The differentiation program responsible for the development of smooth muscle involves the complex interaction of epigenetic and genetic events including chromatin remodeling and acetylation, the SRF-myocar-din pathway, basic helix-loop-helix factors, AP-1 complex genes, and the ternary complex factors of the ETS domain family (Manabe and Owens, 2001;Chen et al, 2002;Du et al, 2003;Kumar and Owens, 2003;Miano, 2003;Wang et al, 2003Wang et al, , 2004Yoshida et al, 2003;Buchwalter et al, 2004;Spin et al, 2004;McDonald et al, 2006;Pipes et al, 2006).…”

Targeting the CB2 cannabinoid receptor in osteoporosis

“…Embryonic male mice that lack functional Shh as a consequence of homozygous mutation fail to show the early inductive budding from the UGS that initiates prostate formation [63,64]. However, it is remarkable that inductive budding can be restored simply by supplementing testosterone to the female mouse ( in vivo ) or to isolated mutant male UGS tissues ( in vitro ) [63].…”