EGF ABROGATION-INDUCED FUSILLI-FORM DYSMORPHOGENESIS OF MECKEL CARTILAGE DURING EMBRYONIC MOUSE MANDIBULAR MORPHOGENESIS IN-VITRO

Mutations associated with genes of the EGF superfamily are implicated in facial malformations arising from abnormal development of the first branchial arch. EGF and EGF receptor (EGFr) transcripts are expressed in the mouse embryonic first branchial arch and derivatives from E9 t hrough E15. EGF transcripts are localized to ectomesenchymal cells ass ociated with precartilage, cartilage, bone and tooth-forming cells. EG F and EGFr proteins co-localize to the same cells suggesting an autocr ine regulation. To test whether EGF effects the timing and positional information required for Meckel's cartilage (MC) and tooth development , we cultured E10 mandibular explants in serumless, chemically defined medium with either antisense or sense EGF oligodeoxynucleotides. Anti sense inhibition of EGF expression produces bilaterally symmetrical Fu silli-form dysmorphogenesis of MC and decreases tooth bud size; these effects are reversed by the addition of exogenous EGF to the culture m edium. Tyrphostin RG 50864, which inhibits EGF receptor kinase activit y, inhibits EGF stimulation of tyrosine phosphorylation in a concentra tion-dependent manner and severely retards mandibular development vet increases tooth size. These findings support the hypothesis that endog enous EGF and EGF-like proteins provide signalling to regulate the siz e and shape both of cartilage and tooth formation during craniofacial morphogenesis.