Functions of PDGF-A and -C: Essential Ligands for the PDGF Alpha Receptor

Altered protein kinase activity is a contributing factor in many diseases including most forms of human malignancies, and there is reason to believe that protein kinases will prove to be major drug targets in the treatment of cancer. Protein kinases mediate most of the signal transduction in eukaryotic cells, regulating cellular events such as transcription, metabolism, proliferation, cytoskeletal rearrangement, migration, differentiation and apoptosis. Protein phosphorylation also plays a critical role in intercellular communication during embryonic development, especially through activation of receptor tyrosine kinases (RTK:s). This study focuses on the Platelet-derived growth factor (PDGF) family, secreted molecules whose functions are to bind to, and activate, two structurally related RTK:s, PDGF receptor alpha and beta. To gain insight into the developmental role of PDGF-A and -C, three lines of mice 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 to lack of alveolar formation. This phenotype was coupled to a loss of alveolar smooth muscle cells and reduced parenchymal elastin, resulting in a picture resembling emphysema. The sixth exon in PDGF-A is normally alternatively spliced, and, when present, it confers binding to extracellular matrix structures. The second line of mice generated carried a mutation in the sixth exon splice acceptor, so that only the short, freely diffusible form of PDGF-A was being produced. Analysis of these mice suggested overlapping functions for PDGF-A and -C, and also revealed that extracellular retention of PDGF-A is important for normal development of gastrointestinal villi. Depending on genetic background, PDGF-C negative mice died postnatally due to a cleft palate accompanied by moderate spina bifida. Interestingly, PDGF-A / PDGF-C double deficient mice were phenotypically indistinguishable from mice carrying a null mutation in PDGF receptor alpha. Taken together, the results of this study imply that PDGF-A and -C are the physiologically important ligands for PDGF receptor alpha during development.