Nonsyndromic clefts of the lip and palate are common birth defects resulting from gene-gene and gene-environment interactions. MSX1 mutations have been linked to orofacial clefting and we show here that Msx1 deficiency causes a growth defect of the medial nasal process (Mnp) in mouse embryos. While this defect alone does not disrupt lip formation, Msx1-deficient embryos develop a cleft lip when the mother is transiently exposed to reduced oxygen levels or to Phenytoin, a drug known to cause embryonic hypoxia. In the absence of interacting environmental factors, the Mnp growth defect caused by Msx1-deficiency is modified by a Pax9-dependent “morphogenetic regulation”, which modulates Mnp shape, rescues lip formation and involves a localised abrogation of Bmp4-mediated repression of Pax9. Analyses of GWAS data revealed a genome-wide significant association of a Gene Ontology morphogenesis term (including assigned roles of MSX1, MSX2, PAX9, BMP4, GREM1) specifically for nonsyndromic cleft lip with cleft palate. Our data indicate that MSX1 mutations may increase the risk for cleft lip formation by interacting with an impaired morphogenetic regulation that adjusts Mnp shape, or through interactions that inhibit Mnp growth.
Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development
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