Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis.
Previous studies have demonstrated that the Hedgehog (Hh) signaling pathway plays a critical role in the development and patterning of many endodermally derived tissues. We have investigated the role of Sonic hedgehog (Shh) in formation of the prostate gland by examining the urogenital phenotype of Shh mutant fetuses. Consistent with earlier work reporting an essential role for Shh in prostate induction, we have found that Shh mutant fetuses display abnormal urogenital development and fail to form prostate buds. Unexpectedly, however, we have discovered that this prostate defect could be rescued by three different methods: renal grafting, explant culture in the presence of androgens, and administration of dihydrotestosterone (DHT) to pregnant mice, indicating that the prostate defect in Shh mutants is due to insufficient levels of androgens. Furthermore, we find that the inhibition of Hh pathway signaling by treatment with cyclopamine does not block prostate formation in explant culture, but instead produces morphological defects consistent with a role for Hh signaling in ductal patterning. Taken together, our studies indicate that the initial organogenesis of the prostate proceeds independently of Shh, but that Shh or other Hh ligands may play a role in subsequent events that pattern the prostate.
Berman
David M
DM
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. dberman@jhmi.edu
Desai
Nishita
N
Wang
Xi
X
Karhadkar
Sunil S
SS
Reynon
Melissa
M
Abate-Shen
Cory
C
Beachy
Philip A
PA
Shen
Michael M
MM
D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D017931:DNA Primers; D013196:Dihydrotestosterone / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000196:embryology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014304:Triolein / Q000494:pharmacology; D014704:Veratrum Alkaloids / Q000494:pharmacology
D000728:Androgens; D017931:DNA Primers; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D013196:Dihydrotestosterone; D014304:Triolein; C000541:cyclopamine