Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity.
The lower jaw skeleton is derived from cephalic neural crest (CNC) cells that reside in the mandibular region of the first pharyngeal arch. Endothelin-A receptor (Ednra) signaling in crest cells is crucial for their development, as Ednra(-/-) mice are born with severe craniofacial defects resulting in neonatal lethality. In this study, we undertook a more detailed analysis of mandibular arch development in Ednra(-/-) embryos to better understand the cellular and molecular basis for these defects. 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. 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. However, a small distal Hand2 expression domain remains. Although this distal expression is not dependent on either Ednra or Dlx5/Dlx6 function, it may require one or more GATA factors. Using fate analysis, we show that these distal Hand2-positive cells probably contribute to lower incisor formation. Together, our results suggest that the establishment of a 'mandibular identity' during lower jaw development requires both Ednra-dependent and -independent signaling pathways.
Department of Molecular, Cellular and Craniofacial Biology and the Birth Defects Center, University of Louisville, Louisville, KY 40292, USA.
Louis-Bruno
LB
Ruest
Xilin
X
Xiang
Kim-Chew
KC
Lim
Giovanni
G
Levi
David E
DE
Clouthier
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D050990:GATA3 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D008334:Mandible / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D044022:Receptor, Endothelin A / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D018398:Homeodomain Proteins; D044022:Receptor, Endothelin A; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; C501120:Dlx5 protein, mouse; C494748:Gata3 protein, mouse; C498766:Hand2 protein, mouse; C501122:dlx5a protein, zebrafish; C410915:hand2 protein, zebrafish