Retinoic acid repression of bone morphogenetic protein 4 in inner ear development.
Bone morphogenetic protein 4 (BMP4) and retinoic acid are important for normal development of the inner ear, but whether they are linked mechanistically is not known. BMP4 antagonists disrupt semicircular canal formation, as does exposure to retinoic acid. We demonstrate that retinoic acid directly down-regulates BMP4 transcription in a mouse inner ear-derived cell line, and we identify a novel promoter in the second intron of the BMP4 gene that is a target of this regulation both in the cell line and in the mouse embryonic inner ear in vivo. The importance of this down-regulation is demonstrated in chicken embryos by showing that the retinoic acid effect on semicircular canal development can be overcome by exogenous BMP4.
Thompson
Deborah L
DL
Department of Internal Medicine, Endocrinology Division, University of Michigan, Ann Arbor, Michigan 48109-0678, USA.
Gerlach-Bank
Lisa M
LM
Barald
Kate F
KF
Koenig
Ronald J
RJ
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D002642:Chick Embryo; D007758:Ear, Inner / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D007438:Introns; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D012313:RNA / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*
D001565:Benzoates; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C082925:retinoic acid receptor beta; D014212:Tretinoin; D012313:RNA; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid