title: Sex specific retinoic acid signaling is required for the initiation of urogenital sinus bud development.
abstract: The mammalian urogenital sinus (UGS) develops in a sex specific manner, giving rise to the prostate in the male and the sinus vagina in the embryonic female. Androgens, produced by the embryonic testis, have been shown to be crucial to this process. In this study we show that retinoic acid signaling is required for the initial stages of bud development from the male UGS. Enzymes involved in retinoic acid synthesis are expressed in the UGS mesenchyme in a sex specific manner and addition of ligand to female tissue is able to induce prostate-like bud formation in the absence of androgens, albeit at reduced potency. Functional studies in mouse organ cultures that faithfully reproduce the initiation of prostate development indicate that one of the roles of retinoic acid signaling in the male is to inhibit the expression of Inhba, which encodes the βA subunit of Activin, in the UGS mesenchyme. Through in vivo genetic analysis and culture studies we show that inhibition of Activin signaling in the female UGS leads to a similar phenotype to that of retinoic acid treatment, namely bud formation in the absence of androgens. Our data also reveals that both androgens and retinoic acid have extra independent roles to that of repressing Activin signaling in the development of the prostate during fetal stages. This study identifies a novel role for retinoic acid as a mesenchymal factor that acts together with androgens to determine the position and initiation of bud development in the male UGS epithelia.
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Bryant
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Francis
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom.
authors.forename: Isabel B
authors.initials: IB
authors.lastname: Lokody
authors.affiliation: Department of Anatomy and Developmental Biology, Clayton, VIC, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Developmental Biology, Clayton, VIC, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Department of Anatomy and Developmental Biology, Clayton, VIC, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, United Kingdom. Electronic address: amanda.swain@icr.ac.uk.
authors.forename: Amanda
authors.initials: A
authors.lastname: Swain
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017931:DNA Primers; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D028322:Inhibin-beta Subunits / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D038081:Organogenesis / Q000502:physiology*; D011467:Prostate / Q000196:embryology; D060888:Real-Time Polymerase Chain Reaction; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D014566:Urogenital System / Q000196:embryology* / Q000378:metabolism; D001616:beta-Galactosidase
chemical_list: D017931:DNA Primers; C103008:inhibin beta A subunit; D028341:Activins; D014212:Tretinoin; D028322:Inhibin-beta Subunits; D001616:beta-Galactosidase
keywords: Organogenesis; Prostate initiation; Sexual differentiation