PDGFRalpha Signaling Requirements in the Development of Tissues Derived From Sclerotome and Dermatome

Abstract

The Platelet-Derived Growth Factor Receptors (PDGFR) play roles in the development of multiple mesenchymal cell types. Upon ligand binding, the receptors signal through a number of intracellular signaling molecules and elicit many cellular responses including migration, proliferation, and differentiation. Studies utilizing tissuespecific deletion permit the elucidation of cell autonomous phenotypes, while analysis of signaling point mutants permits identification of the function of specific downstream effectors. My studies use both methods to uncover the role of PDGFRalpha signaling in the development of skin and bone. An unexplained phenotype of PDGFRalpha null embryos is a defect in the axial skeletal that leads to spina bifida. Using conditional gene deletion I determined that the population of cells responsible for this phenotype is not the chondrocyte but is instead another derivative of the sclerotome. These results demonstrate that signals from adjacent tissues can play important roles in the differentiation of bone populations and identifies an etiology for spina bifida that is not directly caused by neural tube or bone defects. Interestingly, loss of PI3K signaling downstream of PDGFRalpha also results in spina bifida. I found that the sclerotome population described above requires PDGFRalpha signaling to migrate dorsal to the neural tube via PI3K activation. Without this signaling event, downstream effectors including Akt, p70S6K, and PAK1 are not activated and the cells fail to form Rac-associated membrane ruffles. This is the first in vivo evidence that PI3K driven pathways are required for migration downstream of the PDGFRalpha .