An Allelic Series at the PDGFαR Locus Indicates Unequal Contributions of Distinct Signaling Pathways During Development

AbstractA central issue in signal transduction is the physiological contribution of different growth factor-initiated signaling pathways. We have generated knockin mice harboring mutations in the PDGFα receptor (PDGFαR) that selectively eliminate its capacity to activate PI3 kinase (αPI3K) or Src family kinases (αSrc). The αPI3K mutation leads to neonatal lethality due to impaired signaling in many cell types, but the αSrc mutation only affects oligodendrocyte development. A third knockin line containing mutations that eliminate multiple docking sites does not increase the severity of the αPI3K mutation. However, embryos with mutations in the PI3K binding sites of both PDGFRs (α and β) recapitulate the PDGFαR null phenotype. Our results indicate that PI3K has a predominant role in PDGFαR signaling in vivo and that RTK-activated signaling pathways execute both specific and overlapping functions during mammalian development