Glycoprotein 130 Signaling RegulatesNotch1Expression and Activation in the Self-Renewal of Mammalian Forebrain Neural Stem Cells

Abstract

Glycoprotein130 (gp130) and Notch signaling are thought to participate in neural stem cell (NSC) self-renewal. We asked whether gp130 regulates Notch activity in forebrain epidermal growth factor (EGF)-responsive NSCs. Disruption ofNotch1using antisense or a γ-secretase inhibitor demonstrated a requirement forNotch1in the maintenance and proliferation of NSCs. Ciliary neurotrophic factor (CNTF) activation of gp130 in NSCs rapidly increasedNotch1expression. NOTCH1 activation, indicated by tumor necrosis factor α-converting enzyme (TACE)- andpresenilin-mediated processing, also increased. Infusion of EGF+CNTF into adult forebrain lateral ventricles increased periventricular NOTCH1 compared with EGF alone. NeitherHes1(hairyandenhancerofsplit) norHes5appeared to mediate gp130-enhanced NOTCH1 signaling that regulates NSC maintenance. This is the first example of a link between gp130 signaling and NOTCH1 in regulating NSC self-renewal.