Functions of PDGF-A and -C. Essential ligands for the PDGF alpha receptor

Abstract

Altered protein kinase activity is a contributing factor in many diseases including most formsof human malignancies, and there is reason to believe that protein kinases will prove to be majordrug targets in the treatment of cancer. Protein kinases mediate most of the signal transduction ineukaryotic cells, regulating cellular events such as transcription, metabolism, proliferation,cytoskeletal rearrangement, migration, differentiation and apoptosis. Protein phosphorylation alsoplays a critical role in intercellular communication during embryonic development, especiallythrough activation of receptor tyrosine kinases (RTK:s).This study focuses on the Platelet-derived growth factor (PDGF) family, secreted moleculeswhose functions are to bind to, and activate, two structurally related RTK:s, PDGF receptoralpha and beta. To gain insight into the developmental role of PDGF-A and -C, three lines ofmice were generated in which these genes were modified by gene targeting.As a common principle, PDGF-A and -C, secreted from epithelial cells, induced proliferation,and possibly migration, of mesenchymal progenitor cells expressing PDGF receptor alpha.Mice deficient for PDGF-A died perinatally and displayed defective lung development due tolack of alveolar formation. This phenotype was coupled to a loss of alveolar smooth muscle cellsand reduced parenchymal elastin, resulting in a picture resembling emphysema.The sixth exon in PDGF-A is normally alternatively spliced, and, when present, it confersbinding to extracellular matrix structures. The second line of mice generated carried a mutationin the sixth exon splice acceptor, so that only the short, freely diffusible, form of PDGF-A wasbeing produced. Analysis of these mice suggested overlapping functions for PDGF-A and -C, andalso revealed that extracellular retention of PDGF-A is important for normal development ofgastrointestinal villi.Depending on genetic background, PDGF-C negative mice died postnatally due to a cleftpalate accompanied by moderate spina bifida. Interestingly, PDGF-A / PDGF-C double deficientmice were phenotypically indistinguishable from mice carrying a null mutation in PDGFreceptor alpha. Taken together, the results of this study imply that PDGF-A and -C are thephysiologically important ligands for PDGF receptor alpha during development.