Insulin-like growth factor-1 is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2

Neural stem cells (NSCs), when stimulated with epidermal growth factor (EGF ) or fibroblast growth factor-2 (FGF-2), have the capacity to renew, expand , and produce precursors for neurons, astrocytes, and oligodendrocytes. We postulated that the early appearance of insulin-like growth factor (IGF-1) receptors during mouse striatum development implies a role in NSC regulatio n. Thus, we tested in vitro the action of IGF-I on the proliferation of str iatal NSCs. In the absence of IGF-I, neither EGF nor FGF-2 was able to indu ce the proliferation of E14 mouse striatal cells. However, addition of IGF- I generated large proliferative clusters, termed spheres, In a dose-depende nt manner. The newly generated spheres were multipotent, and clonal analysi s revealed that EGF or FGF-2, in the presence of IGF-1, acted directly on N SCs. The actions of IGF-l suggest distinct modes of action of EGF or FGF-2 on NSCs. First, continuous versus delayed administration of these neurotrop hic factors showed that neither IGF-I nor EGF had an effect on NSC survival , whereas FGF-2 promoted the survival or maintenance of the stem cell state of 50% of NSCs for 6 d. Second, shortterm exposure to IGF-I induced the pr oliferation of NSCs In the presence of EGF, but not of FGF-2, through an au tocrine secretion of IGF-I. These findings suggest that IGF-I is a key fact or in the regulation of NSC activation and that EGF and FGF-2 control stria tal NSC proliferation, in part, through distinct intracellular mechanisms.