A functional analyses of PDGF expressed in CNS

Platelet-derived growth factors (PDGFs) and the receptors (PDGFRs) appear to the internal organs of the whole body, and they are distributed in the brain tissue especially widely, and abundantly. They are potent biological molecules with multiple functions, being involved in diverse biological phenomena of our body, and the application to the medical treatment has been hoped for. The present project aimed to understand the functional relevance of PDGFs expressed in the brain through a set of the expression intervention studies.To evade the neonatal lethality in null knockout model, we established the mouse lines of PDGFR-β conditional knockout by Cre-loxP method. This, for the first time, allowed us the functional analyses of the gene in postnatal life. The mutant mice survived after birth and grown up normally, so far examined. However, the mice in which PDGFR-β gene was deleted in neuroepithelium-derived cells, showed increased vulnerability of the brain to the excitotoxicity and cryogenic injuries in which oxidative stress is one of the major cause of death. We could show that PDGF system in the CNS is neuroprotective, and that the effects were mediated by PDGFR-β expressed in neurons in adult mouse brain. We further extended in vivo studies to in vitro, in which we could induce the PDGFR-β gene deletion in cultured cells with non-invasive and stable manner. We could show that the two types of PDGFRs convey similar and distinctive effects in different cells. PDGFR-β but not PDGFR-α specifically mediated migratory response of fibroblasts and the neuronal differentiation of neural stem cells, but inhibited the osteogenic differentiation of mesenchymal stromal cells.Thus, due to the establishment of novel system to appreciate the PDGFR-β gene function, we are starting to reveal the functions that have not been reported. Our project should further give us new vistas to understand the growth factor function in our body.