The temporal genetic hierarchy influencing normal limb development can deregulate and mediate mammalian developmental syndromes. In mice, the limb deformity (ld) locus influences normal limb development and gives rise to alternative mRNAs that can translate into a family of proteins known as formins. Formins play a crucial role in cytoskeletal reorganization by influencing Actin filament assembly. Formins co-localize with the actin cytoskeleton and can translocate into the cell cytosol and into the nucleus in an HGF-dependent manner. Vertebrate nuclear formins can control polarizing activity in limb buds through establishment of a Sonic hedgehog/FGF-4 feedback loop. Deficiency mutations at the mammalian ld locus lead to profound developmental defects in limb and kidney formation. The human Formin 1 and 2 genes map to chromosome 15q13.3 and 1q43, respectively.
