NERVE GROWTH-FACTOR AND NEUROTROPHIN-3 DIFFERENTIALLY REGULATE THE PROLIFERATION AND SURVIVAL OF DEVELOPING RAT-BRAIN OLIGODENDROCYTES

There is increasing evidence that the neurotrophins, particularly nerv e growth factor (NGF) and neurotrophin-3 (NT-3), play a role in the re gulation of glial development in the CNS. Recent studies have shown th at the proliferation of optic nerve-derived O2A progenitors (OLPs) is potentiated by NT-3 in combination with platelet-derived growth factor , whereas NT-3 alone supports the survival of their differentiated pro geny (Barres et al., 1994). In this study, we have examined the expres sion of the high-affinity neurotrophin receptors (trks) and the low-af finity nerve growth factor receptor p75 in developing oligodendrocytes (OLs). In addition, we have examined the effects of NGF and NT-3 on p roliferation and survival of OLPs and OLs, respectively. TrkC, the hig h-affinity NT-3 receptor, and trkA, the high-affinity NGF receptor, ar e both expressed from the early OLP through the mature OL stage. The t runcated form of trkB, lacking the tyrosine kinase domain, and the low -affinity neurotrophin receptor p75 are expressed at low levels in OLP s and are upregulated in mature OLs. NGF and NT-3 both induced the pho sphorylation of mitogen-activated protein kinase (MAPK) in OLPs and in OLs. In both OLPs and OLs, NT-3 sustained the activation of MARK more than NGF. NT-3 enhanced the proliferation of OLPs and supported the s urvival of OLs. By contrast, unless coadministered with FGF-2, NGF did not exhibit mitogenic effects on OLPs but did enhance the survival of differentiated OLs. Our data demonstrate the presence of functional t rkA and trkC in developing OLs and indicate that both NGF and NT-3 hav e a broad spectrum of developmental actions on cells of the OL lineage .