title: Retinoic acid is both necessary for and inhibits myogenic commitment and differentiation in the chick limb.
abstract: Retinoic acid (RA) plays an essential role in the development of many embryonic tissues, including the developing tetrapod limb bud. At early stages of limb development, RA levels are highest proximally and regulate the migration of myoblasts into the limb. As the premyogenic progenitor cells migrate into the limb and accumulate in premuscle masses, they express Pax3 and Meox2. Myogenic differentiation is initiated by expression of Myf5 and MyoD, and both Pax3 and Meox2 are required for normal Myf5 expression. We show by loss of function using the inhibitor citral, that RA signalling within the limb bud is required to maintain Pax3 and Meox2 in the progenitor and Myf5 and MyoD in the differentiating myoblasts. Treatment with excess RA showed a differential effect: Meox2 and Pax3 showed localised down-regulation of expression in the limb. In contrast, there was a dramatic down-regulation of expression of MyoD, Myf5 and Meox1. The down-regulation of myogenic gene expression in response to inhibition of RA signalling, and differential response to application of excess RA, in the absence of changes to cell proliferation and apoptosis, indicate that myogenic specification and differentiation in the developing limb possess a complex sensitivity to RA concentrations.
authors.affiliation: Randall Division of Cell and Molecular Biophysics, New Hunt's House, Kings College London, Guys Campus, London, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Reijntjes
authors.forename: Philippa
authors.initials: P
authors.lastname: Francis-West
authors.forename: Baljinder S
authors.initials: BS
authors.lastname: Mankoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D002642:Chick Embryo / Q000187:drug effects*; D005121:Extremities / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D024510:Muscle Development / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009124:Muscle Proteins; D012333:RNA, Messenger; D014212:Tretinoin