Retinoic acid specifically downregulates Fgf4 and inhibits posterior cell proliferation in the developing mouse autopod.
Retinoic acid, when administered to pregnant mice on d 11.0 of gestation, causes limb skeletal abnormalities consisting of reduced digital number, shortening of the long bones and delayed ossification. We show here that these effects are correlated with a decrease in cell proliferation within 5 h of retinoic acid administration, specifically in the posterior half of the distal limb bud mesenchyme, from which the distal skeletal elements are generated. There is a specific downregulation of Fgf4, a gene known to be involved in limb bud outgrowth and expressed only in the posterior part of the apical ectodermal ridge; Fgf8, which is expressed throughout the apical ectodermal ridge, is unaffected. The reduction in Fgf4 expression is not accompanied by downregulation of Shh, nor of its receptor and downstream target gene Ptc, suggesting that the skeletal reduction defects induced by retinoic acid are mediated specifically by FGF4-induced skeletogenic mesenchymal cell proliferation.
Hayes
C
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Department of Human Anatomy and Genetics, University of Oxford, UK.
Morriss-Kay
G M
GM
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000196:embryology; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D005260:Female; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005552:Forelimb; D005786:Gene Expression Regulation / Q000187:drug effects*; D053823:Hedgehog Proteins; D019044:Image Cytometry; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018878:Limb Buds / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011247:Pregnancy; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014212:Tretinoin / Q000494:pharmacology*
C496457:Fgf8 protein, mouse; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; C112971:fibroblast growth factor 14; D051524:Fibroblast Growth Factor 8; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D001973:Bromodeoxyuridine