The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells.
The cytokines that signal through the common receptor subunit gp130, including ciliary neurotrophic factor (CNTF), interleukin-6, leukemia inhibitory factor (LIF) and oncostatin M, have pleiotropic functions in CNS development. Given the restricted expression domain of the CNTF receptor alpha (CNTFR) in the developing forebrain germinal zone and adult forebrain periventricular area, we have examined the putative role of CNTFR/LIFR/gp130-mediated signaling in regulating forebrain neural stem cell fate in vivo and in vitro. Analysis of LIFR-deficient mice revealed that a decreased level of LIFR expression results in a reduction in the number of adult neural stem cells. In adult LIFR heterozygote (+/-) mice, the number of neural stem cells and their progeny in the forebrain subependyma and TH-immunoreactive neurons in the olfactory bulb were significantly reduced. Intraventricular infusion of CNTF into the adult mouse forebrain, in the absence or presence of epidermal growth factor (EGF), enhanced self-renewal of neural stem cells in vivo. Analyses of EGF-responsive neural stem cells proliferating in vitro found that CNTF inhibits lineage restriction of neural stem cells to glial progenitors, which in turn results in enhanced expansion of stem cell number. These results suggest that CNTFR/LIFR/gp130-mediated signaling supports the maintenance of forebrain neural stem cells, likely by suppressing restriction to a glial progenitor cell fate.
Shimazaki
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T
Genes & Development Research Group, Department of Cell Biology and Anatomy, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1.
Shingo
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Weiss
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D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006579:Heterozygote; D007276:Injections, Intraventricular; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009830:Olfactory Bulb / Q000166:cytology / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D053606:Receptors, OSM-LIF; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; C494200:Il6st protein, mouse; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507841:Lifr protein, mouse; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130; D004815:Epidermal Growth Factor; D014446:Tyrosine 3-Monooxygenase