The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of alpha(v)beta3 integrins.
Central nervous system development requires precise and localized regulation of neural precursor behaviour. Here we show how the interaction between growth factor and integrin signalling pathways provides a mechanism for such precision in oligodendrocyte progenitor (OP) proliferation. While physiological concentrations of platelet-derived growth factor (PDGF) were not in themselves sufficient to promote OP proliferation, they did so on extracellular matrix (ECM) substrates that bind alpha(v)beta3 integrin. Upon PDGF-AA exposure and alpha(v)beta3 engagement, a physical co-association between both receptors was demonstrated, confirming the interaction between these signalling pathways. Furthermore, we found that PDGFalphaR stimulated a protein kinase C-dependent activation of integrin alpha(v)beta3, which in turn induced OP proliferation via a phosphatidylinositol 3-kinase-dependent signalling pathway. These studies establish a mechanism by which OP proliferation is dependent on the availability of both an ECM ligand and a mitogenic growth factor. Growth factor- mediated integrin activation is the critical integrative step in proliferation signalling, and ensures that the response of neural precursor cells to long-range cues can be regulated by their cellular neighbours, allowing precise control of cell behaviour during development.
Baron
Wia
W
Department of Medical Genetics, University of Cambridge, and Cambridge Centre for Brain Repair, ED Adrian Building, University Forvie Site, Cambridge CB2 2PY, UK.
Shattil
Sanford J
SJ
ffrench-Constant
Charles
C
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D008934:Mitogens / Q000494:pharmacology*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D019096:Vitronectin / Q000378:metabolism
D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D019030:Receptors, Vitronectin; D019096:Vitronectin; C075278:platelet-derived growth factor A; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D011493:Protein Kinase C