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Unformatted text preview: 4769 Review Introduction Platelet-derived growth factor (PDGF) was rst identied in a search for serum factors that stimulate the proliferation of arterial smooth muscle cells (Ross et al . , 1974). Since then, mammalian PDGFs have been extensively characterized in culture-based assays, where they have been shown to drive cellular responses including proliferation, survival, migration, and the deposition of extracellular matrix (ECM) and tissue remodeling factors. Knockout studies have demonstrated that many of these cellular responses to PDGFs are essential during mouse development. The genes that encode two ligands, Pdgfa and Pdgfb , and both receptors, PDGF receptor alpha and PDGF receptor beta ( Pdgfra , Pdgfrb ), have been knocked out in the mouse. These studies have demonstrated that PDGFB and PDGFR are essential for the development of support cells in the vasculature, whereas PDGFA and PDGFR are more broadly required during embryogenesis, with essential roles in numerous contexts, including central nervous system, neural crest and organ development (Leven et al . , 1994; Soriano, 1994; Bostrm et al . , 1996; Soriano, 1997; Fruttiger et al . , 1999; Karlsson et al . , 1999; Gnessi et al . , 2000; Karlsson et al . , 2000). Because of the severe and pleiotropic phenotypes of Pdgfa and Pdgfra knockout mouse embryos, many primary functions of PDGFs remained elusive until being addressed in experiments using conditional gene ablation and gain-of-function transgenics. Pdgfr signaling mutants have also been generated in which specic tyrosine residues in the receptor cytoplasmic domains have been mutated to phenylalanines. These mutations disrupt the interactions of PDGFRs with individual cytoplasmic signaling proteins and, in some cases, abrogate a subset of receptor functions (Heuchel et al., 1999; Tallquist et al., 2000; Klinghoffer et al . , 2002) (M. Tallquist and P.S., unpublished). Together, such in vivo studies have demonstrated that the PDGFs perform distinct cellular roles at successive stages of mouse embryogenesis. In many contexts, PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations (reviewed by Betsholtz et al . , 2001). During later maturation stages, PDGF signaling has been implicated in tissue remodeling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In mouse and Drosophila , PDGFs also direct cell migration, both at short and long distances from signal sources. This review discusses the known roles of PDGFs in development, with emphasis on cellular responses to PDGFs and how they contribute to neural/oligodendrocyte development, vascular and hematopoietic development, neural crest cell development, organogenesis, somitogenesis and skeletal patterning. Although most published studies of PDGF functions in vivo have been performed in mouse, early studies of PDGF- and PDGFR-related proteins in other model...
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