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Gene Review

Dlx6  -  distal-less homeobox 6

Mus musculus

Synonyms: Homeobox protein DLX-6
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High impact information on Dlx6

  • Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice [1].
  • The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development [2].
  • Consistent with this conclusion, Dlx6 was down-regulated in branchial arches from EdnrA mutant mice [3].
  • These structural changes are preceded by aberrant expansion of proximal first arch gene expression into the distal arch, in addition to the previously described loss of a Dlx6/Hand2 expression network [4].
  • Furthermore, bosentan, a pharmacological inhibitor of Endothelin-1 signaling caused a loss of I56i-lacZ expression in the most distal aspects of the expression domain, corresponding to the area of Dlx-6 expression previously shown to be under the control of Endothelin-1 [5].

Biological context of Dlx6

  • To determine if the overlaps are a result of the conservation of enhancer sequences between paralogous clusters, we compared the Dlx1/2 and the Dlx5/Dlx6 intergenic regions from human, mouse, zebrafish, and from two pufferfish, Spheroides nephelus and Takifugu rubripes [6].
  • As morphogenesis proceeds, Dlx5 and Dlx6 expression is seen throughout the forming semicircular canals and endolymphatic structures [7].
  • DLX homeobox proteins bind differentially to the Dlx5/Dlx6 intergenic enhancer in newborn retina (DLX2) and embryonic striatum (DLX1, DLX2) in situ [8].
  • By comparing protein binding to these sites in branchial arch extracts from endothelin receptor A (EdnrA) mutant and wild-type mouse embryos, we identified Dlx6, a member of the Distal-less family of homeodomain proteins, as an ET-1-dependent binding factor [3].
  • Dlx5 and Dlx6, two members of the Distalless gene family, are required for development of numerous tissues during embryogenesis, including facial and limb development [9].

Anatomical context of Dlx6

  • Dlx5 and Dlx6 expression in the developing inner ear is first seen at stages 12 and 13, respectively, in the rim of the otic pit, before spreading throughout the dorsal otocyst [7].
  • In addition, Dlx5 and Dlx6 are expressed in differentiating osteoblasts [10].
  • It was found that expression of the mouse Dlx6 gene takes place in the rostral ectoderm and presumptive olfactory and otic placodes with patterns similar to the previously reported expression of the physically linked Dlx5 gene [11].
  • We show that most lower jaw structures in Ednra(-/-) embryos undergo a homeotic transformation into maxillary-like structures similar to those observed in Dlx5/Dlx6(-/-) embryos, though lower incisors are still present in both mutant embryos [4].
  • Targeted inactivation of Dlx5 and Dlx6 in mice results in multiple developmental defects in craniofacial and limb structures, suggesting that these genes are crucial for aspects of both neural crest and nonneural crest development [9].


  1. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Horike, S., Cai, S., Miyano, M., Cheng, J.F., Kohwi-Shigematsu, T. Nat. Genet. (2005) [Pubmed]
  2. The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Robledo, R.F., Rajan, L., Li, X., Lufkin, T. Genes Dev. (2002) [Pubmed]
  3. Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer. Charité, J., McFadden, D.G., Merlo, G., Levi, G., Clouthier, D.E., Yanagisawa, M., Richardson, J.A., Olson, E.N. Genes Dev. (2001) [Pubmed]
  4. Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity. Ruest, L.B., Xiang, X., Lim, K.C., Levi, G., Clouthier, D.E. Development (2004) [Pubmed]
  5. Intergenic enhancers with distinct activities regulate Dlx gene expression in the mesenchyme of the branchial arches. Park, B.K., Sperber, S.M., Choudhury, A., Ghanem, N., Hatch, G.T., Sharpe, P.T., Thomas, B.L., Ekker, M. Dev. Biol. (2004) [Pubmed]
  6. Regulatory roles of conserved intergenic domains in vertebrate Dlx bigene clusters. Ghanem, N., Jarinova, O., Amores, A., Long, Q., Hatch, G., Park, B.K., Rubenstein, J.L., Ekker, M. Genome Res. (2003) [Pubmed]
  7. Dlx gene expression during chick inner ear development. Brown, S.T., Wang, J., Groves, A.K. J. Comp. Neurol. (2005) [Pubmed]
  8. Identification of a direct Dlx homeodomain target in the developing mouse forebrain and retina by optimization of chromatin immunoprecipitation. Zhou, Q.P., Le, T.N., Qiu, X., Spencer, V., de Melo, J., Du, G., Plews, M., Fonseca, M., Sun, J.M., Davie, J.R., Eisenstat, D.D. Nucleic Acids Res. (2004) [Pubmed]
  9. Dlx5/6-enhancer directed expression of Cre recombinase in the pharyngeal arches and brain. Ruest, L.B., Hammer, R.E., Yanagisawa, M., Clouthier, D.E. Genesis (2003) [Pubmed]
  10. Multiple functions of Dlx genes. Merlo, G.R., Zerega, B., Paleari, L., Trombino, S., Mantero, S., Levi, G. Int. J. Dev. Biol. (2000) [Pubmed]
  11. Differential expression of orthologous Dlx genes in zebrafish and mice: implications for the evolution of the Dlx homeobox gene family. Quint, E., Zerucha, T., Ekker, M. J. Exp. Zool. (2000) [Pubmed]
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