Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7563-8. doi: 10.1073/pnas.1603930113. Epub 2016 Jun 22.


Cranial neural crest cells (crNCCs) migrate from the neural tube to the pharyngeal arches (PAs) of the developing embryo and, subsequently, differentiate into bone and connective tissue to form the mandible. Within the PAs, crNCCs respond to local signaling cues to partition into the proximo-distally oriented subdomains that convey positional information to these developing tissues. Here, we show that the distal-most of these subdomains, the distal cap, is marked by expression of the transcription factor Hand1 (H1) and gives rise to the ectomesenchymal derivatives of the lower incisors. We uncover a H1 enhancer sufficient to drive reporter gene expression within the crNCCs of the distal cap. We show that bone morphogenic protein (BMP) signaling and the transcription factor HAND2 (H2) synergistically regulate H1 distal cap expression. Furthermore, the homeodomain proteins distal-less homeobox 5 (DLX5) and DLX6 reciprocally inhibit BMP/H2-mediated H1 enhancer regulation. These findings provide insights into how multiple signaling pathways direct transcriptional outcomes that pattern the developing jaw.

Keywords: Bmp; DLX; HAND1; cranial neural crest cells; development.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Bone Morphogenetic Proteins / metabolism*
  • Enhancer Elements, Genetic
  • GATA Transcription Factors / metabolism
  • Genes, Reporter
  • Homeodomain Proteins / metabolism*
  • Mandible / embryology*
  • Mandible / metabolism
  • Mice, Transgenic
  • Molecular Sequence Data
  • Smad Proteins / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Bone Morphogenetic Proteins
  • Dlx5 protein, mouse
  • Dlx6 protein, mouse
  • GATA Transcription Factors
  • Hand1 protein, mouse
  • Hand2 protein, mouse
  • Homeodomain Proteins
  • Smad Proteins