Growth factor signaling specificity in mouse development

Among the best understood growth factor regulated pathways are those mediated by receptor tyrosine kinases. We have chosen to focus on signaling pathways that regulate neural crest and vascular development. To elucidate the importance of individual signaling pathways in mediating PDGF and FGF responses, we have generated allelic series at the PDGFRα/Rβ or FGFR1 loci in which docking sites for various effectors have been mutated. Loss of one or several docking sites leads to hypomorphic mutations of increasing severity. These results might help distinguish between qualitative or quantitative models for signaling modules in mediating growth factor responses. To identify critical targets of PDGF in development, we have designed a new expression‐driven screening platform by combining gene trapping with microarray technology, providing a fast track from gene identification to functional validation. Preliminary phenotypic analysis has revealed phenotypes reminiscent of PDGF null or hypomorphic mutation in most of the target mutant mice generated. We are presently investigating cross‐talk between PDGF and ephrin signaling pathways. Our studies have been focused on the roles of ephrin‐B1/B2 forward and reverse signaling in neural crest cells. Our results have shown that ephrin‐B1 plays important roles in craniofacial development and that ephrin‐B2 regulates trunk neural crest cell migration.