Essential role of Gab1 for signaling by the c-Met receptor in vivo

The docking protein Gab1 binds phosphorylated c-Met receptor tyrosine kinas e directly and mediates signals of c-Met in cell culture. Gab1 is phosphory lated by c-Met and by other receptor and nonreceptor tyrosine kinases, Here , we report the functional analysis of Gab1 by targeted mutagenesis in the mouse, and compare the phenotypes of the Gab1 and c-Met mutations. Gab1 is essential for several steps in development: migration of myogenic precursor cells into the limb anlage is impaired in Gab1-/- embryos. As a consequenc e, extensor muscle groups of the forelimbs are virtually absent, and the fl exor muscles reach less far. Fewer hindlimb muscles exist, which are smalle r and disorganized. Muscles in the diaphragm, which also originate from mig ratory precursors, are missing. Moreover, Gab1-/- embryos die in a broad ti me window between E13.5 and E18.5, and display reduced liver size and place ntal defects. The labyrinth layer, but not the spongiotrophoblast layer, of the placenta is severely reduced, resulting in impaired communication betw een maternal and fetal circulation. Thus, extensive similarities between th e phenotypes of c-Met and HGF/SF mutant mice exist: and the muscle migratio n phenotype is even more pronounced in Gab1-/-:c-Met+/- embryos. This is ge netic evidence that Gab1 is essential for c-Met signaling in vivo. Analogy exists to signal transmission by insulin receptors, which require IRS1 and IRS2 as specific docking proteins.