Getting your head on straight in a Dlx wonderland

The branchial arches (BAs) are segmentally repeated structures in the embryonic vertebrate head arising from the ventrolateral surfaces. It has been thought that a prototypical gnathostome (jawed vertebrate) BA likely contained a proximodistal series of five chondrocranial skeletal elements and that subsequent evolution has modified this pattern. These elements are further associated with an ordered series of dermatocranial bones. The most rostral arch (BA1) gives rise to most, though not all, of the jaw apparatus and associated soft tissues. BA1 has two principal proximodistal subdivisions, the maxillary (mxBA1, proximal) and mandibular (mdBA1, distal) arches, that contribute to the upper and lower jaws, respectively. Patterning of the BA requires the establishment of both inter-BA and intra-BA identities. Evidence implicates Hox, Pbx, and Otx homeobox gene regulation in the former task; less attention has been paid to the latter task. The six mammalian Distal-less homeobox (Dlx ) genes have been considered candidate regulators of the latter task. The Dlx genes are genomically linked, convergently transcribed gene pairs (Dlx2/1, Dlx5/6 and Dlx3/7) that share regulatory elements and similar expression patterns. In the BA mesenchyme, the Dlx gene pairs are expressed in nested patterns: Dlx1/2 throughout most of the proximodistal axis, with Dlx5/6 and Dlx3/7 progressively restricted distally. The correlation of this nested expression pattern with a proximodistal BA skeletal series suggests the hypothesis that a Dlx code establishes identity within this series. Previously, this notion has been addressed by the generation of Dlx1 -/-, Dlx2-/-, and Dlx1/2-/- mutant mice. Dlx1-/-, Dlx2 -/-, and Dlx1/2-/- mice evince progressively more severe alterations of the skeletal elements derived from proximal BAs; yet, although Dlx1 and Dlx2 are expressed in distal BAs, derivative distal structures were reported to appear normal in these mutants. Among the many questions that arose following these initial loss of function studies of Dlx1, Dlx2 , and Dlx1/2 were: (1) do any Dlx genes contribute to the development, pattern, and morphogenesis of the distal derivatives of the BAs; and (2) do distally restricted (nested) Dlx genes genetically compensate for Dlx1 and Dlx2 with regard to distal BA development? The work presented herein assess the hypothesized combinatorial code by addressing these two basic questions. (Abstract shortened by UMI.).