Death in Hospital

Abstract

<h3>Summary</h3> FGFs are key developmental regulators which typically direct cell proliferation, survival, and migration following the engagement of tyrosine kinase receptors. We find that coordinate loss of <i>Fgfr1</i> and <i>Fgfr2</i> in cranial neural crest cells results in facial clefting and mandibular defects with high levels of apoptosis, and that suppressing cell death alleviates the mutant phenotype. To identify critical downstream signaling pathways that regulate these processes, we generated allelic series of knock-in point mutations in each gene that disrupt binding of signaling effectors to the receptors, alone or in combination, as well as a kinase dead allele of <i>Fgfr2</i> which broadly phenocopies the null mutant. While signaling mutations in either receptor, even when combined, failed to recapitulate the null mutant phenotypes, they revealed discrete roles for various pathways in regulating specific aspects of craniofacial development. We furthermore found that these signaling mutations together abrogate multiple established FGF-induced signal transduction pathways, while other FGF functions such as cell-matrix and cell-cell adhesion remain unaffected. Our studies establish combinatorial roles of both <i>Fgfr1</i> and <i>Fgfr2</i> in development and identify novel kinase-dependent cell adhesion properties for FGF receptors, beyond their well-established roles in intracellular signaling.