Role of Retinoic Acid Signaling, FGF Signaling and Genes in Control of Limb Development.

The function of retinoic acid (RA) during limb development is still debated, as loss and gain of function studies led to opposite conclusions. With regard to limb initiation, genetic studies demonstrated that activation of FGF10 signaling is required for the emergence of limb buds from the trunk, with and RA signaling acting upstream in the forelimb field, whereas and act upstream in the hindlimb field. Early studies in chick embryos suggested that RA as well as and () are required for subsequent proximodistal patterning of both forelimbs and hindlimbs, with RA diffusing from the trunk, functioning to activate specifically in the proximal limb bud mesoderm. However, genetic loss of RA signaling does not result in loss of limb expression and limb patterning is normal, although expression is reduced in trunk somitic mesoderm. More recent studies demonstrated that global genetic loss of results in a somite defect and failure of limb bud initiation. Other new studies reported that conditional genetic loss of in the limb results in proximodistal patterning defects, and distal FGF8 signaling represses to constrain its expression to the proximal limb. In this review, we hypothesize that RA and both function in the trunk to initiate forelimb bud initiation, but that limb expression is activated proximally by a factor other than RA and repressed distally by FGF8 to generate proximodistal patterning.