TY - JOUR
T1 - Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice
AU - Clouthier, David E.
AU - Williams, S. Clay
AU - Yanagisawa, Hiromi
AU - Wieduwilt, Matthew
AU - Richardson, James A
AU - Yanagisawa, Masashi
N1 - Funding Information:
We thank Jane Johnson for critically reading the manuscript; Shelly Dixon for technical assistance; Deepak Srivastava for the dHAND, eHAND, Mhox, and Ufd1L probes; Kathleen Mahon for the Dlx-2 and Dlx-3 probes; Christo Goridis for the Barx1 probe; Kirk Thomas for the Hoxa-2 probe; Trevor Williams for the AP-2 probe; and Vincent Giguere for the CRABP-1 probe. M.Y. is an Investigator, and D.E.C. is an Associate, of the Howard Hughes Medical Institute. This work was supported in part by research grants from the Perot Family Foundation and the W. M. Keck Foundation.
PY - 2000/1/1
Y1 - 2000/1/1
N2 - Most of the bone and cartilage in the craniofacial region is derived from cephalic neural crest cells, which undergo three primary developmental events: migration from the rhombomeric neuroectoderm to the pharyngeal arches, proliferation as the ectomesenchyme within the arches, and differentiation into terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can lead to craniofacial malformation. We have previously shown that the G-protein-coupled endothelin-A receptor (ET(A)) is expressed in the neural crest-derived ectomesenchyme, whereas the cognate ligand for ET(A), endothelin-1 (ET-1), is expressed in arch epithelium and the paraxial mesoderm-derived arch core; absence of either ET(A) or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neural crest development is disrupted in ET(A)- deficient embryos. We find that, while neural crest cell migration in the head of ET(A)(-/-) embryos appears normal, expression of a number of transcription factors in the arch ectomesenchymal cells is either absent or significantly reduced. These ET(A)-dependent factors include the transcription factors goosecoid, Dlx-2, Dlx-3, dHAND, eHAND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the size of the arches in E10.5 to E11.5 ET(A)(-/-) embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ET(A) signaling in ectomesenchymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesenchyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells apoptosis. In particular, this developmental pathway appears distinct from the pathway that includes UFD1L, implicated as a causative gene in CATCH 22 patients, and suggests parallel complementary pathways mediating craniofacial development.
AB - Most of the bone and cartilage in the craniofacial region is derived from cephalic neural crest cells, which undergo three primary developmental events: migration from the rhombomeric neuroectoderm to the pharyngeal arches, proliferation as the ectomesenchyme within the arches, and differentiation into terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can lead to craniofacial malformation. We have previously shown that the G-protein-coupled endothelin-A receptor (ET(A)) is expressed in the neural crest-derived ectomesenchyme, whereas the cognate ligand for ET(A), endothelin-1 (ET-1), is expressed in arch epithelium and the paraxial mesoderm-derived arch core; absence of either ET(A) or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neural crest development is disrupted in ET(A)- deficient embryos. We find that, while neural crest cell migration in the head of ET(A)(-/-) embryos appears normal, expression of a number of transcription factors in the arch ectomesenchymal cells is either absent or significantly reduced. These ET(A)-dependent factors include the transcription factors goosecoid, Dlx-2, Dlx-3, dHAND, eHAND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the size of the arches in E10.5 to E11.5 ET(A)(-/-) embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ET(A) signaling in ectomesenchymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesenchyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells apoptosis. In particular, this developmental pathway appears distinct from the pathway that includes UFD1L, implicated as a causative gene in CATCH 22 patients, and suggests parallel complementary pathways mediating craniofacial development.
KW - Apoptosis
KW - G-protein-coupled receptor
KW - Neural crest cells
KW - Pharyngeal arch
UR - http://www.scopus.com/inward/record.url?scp=0033959164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033959164&partnerID=8YFLogxK
U2 - 10.1006/dbio.1999.9527
DO - 10.1006/dbio.1999.9527
M3 - Article
C2 - 10625532
AN - SCOPUS:0033959164
SN - 0012-1606
VL - 217
SP - 10
EP - 24
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -