The D1x5 and D1x6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development

Abstract

D1x homeobox genes are mammalian homologs of the Drosophila Distal-less (D11) gene. The D1x/D11 gene family is of ancient origin and appears to play a role in appendage development in essentially all species in which it has been identified. In Drosophila, D11 is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human D1x5 and D1x6 homeobox genes have been identified as possible candidate genes for the autosomal dominant form of the split- hand/split-foot malformation (SHFM), a heterogeneous limb disorder characterized by missing central digits and claw-like distal extremities. Targeted inactivation of D1x5 and D1x6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, D1x/D11 gene products are shown to be critical regulators of mammalian limb development, as combined loss-of-function mutations phenocopy SHFM. Furthermore, spatiotemporal-specific transgenic overexpression of D1x5, in the apical ectodermal ridge of D1x5/6 null mice can fully rescue D1x/D11 function in limb outgrowth.