Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Development. 2014 Aug;141(15):3050-61. doi: 10.1242/dev.107680.


In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a non-cell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.

Keywords: Craniofacial development; Dimerization; Hand1; Neural crest; Phosphorylation; Transcription; bHLH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Body Patterning / genetics
  • Branchial Region / metabolism
  • Face / embryology
  • Female
  • Fibroblast Growth Factor 8 / genetics
  • Gene Expression Regulation, Developmental*
  • Genotype
  • Hedgehog Proteins / genetics
  • Male
  • Mice
  • Morphogenesis / physiology
  • Mutation
  • Neural Crest / embryology*
  • Nuclear Proteins / genetics
  • Phenotype
  • Phosphorylation
  • Protein Multimerization
  • Signal Transduction
  • Skull / embryology*
  • Twist-Related Protein 1 / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Fgf8 protein, mouse
  • Hand1 protein, mouse
  • Hedgehog Proteins
  • Nuclear Proteins
  • Shh protein, mouse
  • Twist-Related Protein 1
  • Twist1 protein, mouse
  • Fibroblast Growth Factor 8