The <i>Dlx5</i> and <i>Dlx6</i> homeobox genes are essential for craniofacial, axial, and appendicular skeletal development

TLDR

Dlx homeobox genes, mammalian homologs of the Drosophila Distal‑less gene, are ancient regulators of appendage development expressed in distal regions of developing limbs across species. The study investigates human Dlx5 and Dlx6 as candidate genes for autosomal dominant split‑hand/split‑foot malformation, a limb disorder marked by missing central digits and claw‑like extremities. Loss of Dlx5 and Dlx6 in mice produces severe craniofacial, axial, and appendicular skeletal defects, perinatal lethality, and limb phenotypes that recapitulate SHFM, while targeted Dlx5 overexpression in the apical ectodermal ridge restores normal limb outgrowth.

Abstract

Dlx homeobox genes are mammalian homologs of the Drosophila Distal-less ( Dll ) gene. The Dlx / Dll 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 , Dll is expressed in the distal portion of the developing appendages and is critical for the development of distal structures. In addition, human Dlx5 and Dlx6 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 Dlx5 and Dlx6 genes in mice results in severe craniofacial, axial, and appendicular skeletal abnormalities, leading to perinatal lethality. For the first time, Dlx / Dll 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 Dlx5 , in the apical ectodermal ridge of Dlx5/6 null mice can fully rescue Dlx / Dll function in limb outgrowth.