The BMP antagonists Chordin and Noggin have essential but redundant roles in mouse mandibular outgrowth.
Here we investigate the roles of the Bone Morphogenetic Protein (BMP) antagonists Chordin and Noggin in development of the mandible, which is derived from the first branchial arch (BA1). Both genes are expressed in the pharynx during early mandibular outgrowth and later in the mandibular process. Mice mutant for either Nog or Chd have only mild mandibular defects; however, pups of the genotype Chd(-/-);Nog(+/-) exhibit a range of mandibular truncation phenotypes, from normal to agnathia. A few embryos homozygous null for both genes survive to late gestation; many are agnathic, though a few have significant mandibular outgrowth. In mandibular explants, ectopic BMP4 rapidly induces expression of both Chd and Nog, consistent with results obtained in vivo with mutant embryos. Previous work has shown that FGF8 is a survival factor for cells populating the mandibular bud. We find that excess BMP4 represses Fgf8 transcription in mandibular explants. Embryos lacking these BMP antagonists often show a strong reduction in Fgf8 expression in the pharyngeal ectoderm, and increased cell death in the mandibular bud. We suggest that the variable mandibular hypoplasia in double mutants involves increased BMP activity downregulating Fgf8 expression in the pharynx, decreasing cell survival during mandibular outgrowth.
Stottmann
R W
RW
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Anderson
R M
RM
Klingensmith
J
J
D000818:Animals; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D001934:Branchial Region / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002352:Carrier Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008334:Mandible / Q000002:abnormalities / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C496457:Fgf8 protein, mouse; C054234:chordin