Functions of platelet-derived growth factor and its receptors deduced from gene inactivation in mice

Platelet-derived growth factor (PDGF) is a family of growth factors for mesenchymal and glia cells. PDGF and PDGF receptor expression patterns, the use of antagonists, and genetic approaches involving targeted inactivation of PDGF and PDGF receptor genes have implicated PDGFs as critical factors in a number of developmental and disease processes. This review summarizes the current understanding of the biological roles of the PDGF family of growth factors, with emphasis on their role in mammalian embryonic development. PDGF-A, acting through its receptor PDGFR-alpha, is involved in epithelium-to-mesenchyme signaling. This leads to proliferation of specific populations of mesenchymal cells, which in turn play critical roles in the development of the epithelium. PDGF-A/PDGFR-alpha interaction is also critical in the developing central nervous system as a rate-limiting mitogenic stimulus for oligodendrocyte progenitors. Accordingly, lack of PDGF-A in mice leads to defects in many organs, including lung, skin, intestine, testis, and brain, and to death in early postnatal life. PDGF-B and PDGFR-beta have essential roles in the recruitment of vascular smooth muscle cells and pericytes to newly formed blood vessels. PDGF-B is expressed by the endothelial cells in growing blood vessels, and promotes proliferation and migration of PDGFR-beta -positive smooth muscle/pericyte progenitors. A novel PDGF, PDGF-C, was recently discovered and demonstrated to be a high affinity ligand and agonist for PDGFR-alpha. PDGFR-alpha null mice show a series of severe defects, which are not seen in PDGF-A null mice or in mice lacking both PDGF-A and PDGF-B. It is possible that these defects reflect ant embryonic role for PDGF-C. PDGF-C is expressed at many sites in the developing mouse embryo. In the developing kidney the pattern of PDGF-C expression correlates well with a defect which is seen in PDGFR-alpha null mice but missing in PDGF-A and PDGF-B-deficient mice.