Role of D1x6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer

Jeroen Charité, David G McFadden, Giorgio Merlo, Giovanni Levi, David E. Clouthier, Masashi Yanagisawa, James A Richardson, Eric N Olson

Research output: Contribution to journalArticlepeer-review

118 Scopus citations


Neural crest cells play a key role in craniofacial development. The endothelin family of secreted polypeptides regulates development of several neural crest sublineages, including the branchial arch neural crest. The basic helix-loop-helix transcription factor dHAND is also required for craniofacial development, and in endothelin-1 (ET-1) mutant embryos, dHAND expression in the branchial arches is down-regulated, implicating it as a transcriptional effector of ET-1 action. To determine the mechanism that links ET-1 signaling to dHAND transcription, we analyzed the dHAND gene for cis-regulatory elements that control transcription in the branchial arches. We describe an evolutionarily conserved dHAND enhancer that requires ET-1 signaling for activity. This enhancer contains four homeodomain binding sites that are required for branchial arch expression. 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. Consistent with this conclusion, Dlx6 was down-regulated in branchial arches from EdnrA mutant mice. These results suggest that Dlx6 acts as an intermediary between ET-1 signaling and dHAND transcription during craniofacial morphogenesis.

Original languageEnglish (US)
Pages (from-to)3039-3049
Number of pages11
JournalGenes and Development
Issue number22
StatePublished - Nov 15 2001


  • Branchial arches
  • D1x6
  • Endothelin receptor A
  • Endothelin-1
  • Neural crest

ASJC Scopus subject areas

  • General Medicine


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