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, c auses limb skeletal abnormalities consisting of reduced digital number, sho rtening 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 di stal limb bud mesenchyme, from which the distal skeletal elements are gener ated. There is a specific downregulation of Fgf4, a gene known to be involv ed in limb bud outgrowth and expressed only in the posterior part of the ap ical ectodermal ridge; Fgf8, which is expressed throughout the apical ectod ermal ridge, is unaffected. The reduction in Fgf4 expression is not accompa nied by downregulation of Shh, nor of its receptor and downstream target ge ne Ptc, suggesting that the skeletal reduction defects induced by retinoic acid are mediated specifically by FGF4-induced skeletogenic mesenchymal cel l proliferation.