Nature Genetics
22, 69 - 73 (1999)
doi:10.1038/8773
Epidermal growth factor receptor function is necessary for normal craniofacial
development and palate closurePäivi J. Miettinen1, 5, Jennie R. Chin2, Lillian Shum3, Harold C. Slavkin3, Charles F. Shuler4, Rik Derynck1, 2
& Zena Werb21
Department of Growth and Development, University of California, San Francisco, California 94143-0452, USA. 2
Department of Anatomy, and Programs in Cell Biology and Developmental Biology, University of California, San Francisco, California 94143-0452, USA. 3
Craniofacial Development Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland 20892-2745, USA. 4
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, California 90025, USA. 5
Present address: Department of Pathology, Haartman Institute, University of Helsinki, Finland.
Correspondence should be addressed to Päivi J. Miettinen paivi.miettinen@helsinki.fiCraniofacial malformations are among the most frequent congenital birth
defects in humans; cleft palate, that is inadequate fusion of the palatal
shelves, occurs with an annual incidence of 1 in 700 to 1 in 1,000 live births
among individuals of European descent1. The secondary palate
arises as bilateral outgrowths from the maxillary processes2,
and its formation depends on the coordinated development of craniofacial structures
including the Meckel's cartilage and the mandible3. Cleft lip
and palate syndromes in humans are associated with polymorphisms in the gene
(TGFA) encoding transforming growth factor- (TGF-), an
epidermal growth factor receptor (EGFR) ligand made by most epithelia1,
4. Here we have characterized craniofacial development in Egfr
-deficient (Egfr-/-) mice. Newborn Egfr
-/- mice have facial mediolateral defects including narrow, elongated
snouts, underdeveloped lower jaw and a high incidence of cleft palate. Palatal
shelf explants from Egfr-/- mice fused, but frequently
had residual epithelium in the midline. In addition, morphogenesis of Meckel's
cartilage was deficient in cultured mandibular processes from Egfr
-/- embryos. The secretion of matrix metalloproteinases (MMPs)
was diminished in Egfr-/- explants, consistent with
the ability of EGF to increase MMP secretion and with the decreased MMP expression
caused by inhibition of Egfr signalling in wild-type explants. Accordingly,
inactivation of MMPs in wild-type explants phenocopied the defective morphology
of Meckel's cartilage seen in Egfr-/- explants. Our
results indicate that EGFR signalling is necessary for normal craniofacial
development and that its role is mediated in part by its downstream targets,
the MMPs, and may explain the genetic correlation of human cleft palate with
polymorphisms in TGFA.
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