title: BMP action in skeletogenesis involves attenuation of retinoid signaling.
abstract: The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hoffman
authors.forename: Kamal
authors.initials: K
authors.lastname: Garcha
authors.forename: Konstantina
authors.initials: K
authors.lastname: Karamboulas
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Cowan
authors.forename: Linsay M
authors.initials: LM
authors.lastname: Drysdale
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
mesh_terms: D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D019902:Chondrocytes / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D018878:Limb Buds; D051379:Mice; D009924:Organ Culture Techniques; D010012:Osteogenesis / Q000502:physiology*; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012176:Retinoids / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase