Glycoprotein 130 signaling regulates Notch1 expression and activation in the self-renewal of mammalian forebrain neural stem cells.
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 of Notch1 using antisense or a gamma-secretase inhibitor demonstrated a requirement for Notch1 in the maintenance and proliferation of NSCs. Ciliary neurotrophic factor (CNTF) activation of gp130 in NSCs rapidly increased Notch1 expression. NOTCH1 activation, indicated by tumor necrosis factor alpha-converting enzyme (TACE)- and presenilin-mediated processing, also increased. Infusion of EGF+CNTF into adult forebrain lateral ventricles increased periventricular NOTCH1 compared with EGF alone. Neither Hes1 (hairy and enhancer of split) nor Hes5 appeared 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.
Chojnacki
Andrew
A
Genes & Development Research Group, Department of Cell Biology and Anatomy, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1.
Shimazaki
Takuya
T
Gregg
Christopher
C
Weinmaster
Gerry
G
Weiss
Samuel
S
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D010450:Endopeptidases / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology*; D012333:RNA, Messenger / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors
D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; C494200:Il6st protein, mouse; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D014157:Transcription Factors; D050822:Cytokine Receptor gp130; D004815:Epidermal Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse