title: A growth-promoting signaling component cyclin D1 in neural stem cells has antiastrogliogenic function to execute self-renewal.
abstract: Self-renewing proliferation of neural stem cells (NSCs) is intimately linked to the inhibition of neuronal and glial differentiation, however, their molecular linkage has been poorly understood. We have proposed a model previously explaining partly this linkage, in which fibroblast growth factor 2 (FGF2) and Wnt signals cooperate to promote NSC self-renewal via β-catenin accumulation, which leads to the promotion of proliferation by lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated cyclin D1 expression and at the same time to the inhibition of neuronal differentiation by β-catenin-mediated potentiation of Notch signaling. To fully understand the mechanisms underlying NSC self-renewal, it needs to be clarified how these growth factor signals inhibit glial differentiation as well. Here, we demonstrate that cyclin D1, a NSC growth promoting signaling component and also a common component of FGF2 and Wnt signaling pathways, inhibits astroglial differentiation of NSCs. Interestingly, this effect of cyclin D1 is mediated even though its cell cycle progression activity is blocked. Forced downregulation of cyclin D1 enhances astrogliogenesis of NSCs in culture and in vivo. We further demonstrate that cyclin D1 binds to STAT3, a transcription factor downstream of astrogliogenic cytokines, and suppresses its transcriptional activity on the glial fibrillary acidic protein (Gfap) gene. Taken together with our previous finding, we provide a novel molecular mechanism for NSC self-renewal in which growth promoting signaling components activated by FGF2 and Wnts inhibit neuronal and glial differentiation.
authors.affiliation: Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Bizen
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tabu
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Kagawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taga
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D005904:Glial Fibrillary Acidic Protein; D053605:Leukemia Inhibitory Factor; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; D051176:beta Catenin; C528900:glial fibrillary astrocytic protein, mouse; D019938:Cyclin D1; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Astrocyte differentiation; Cyclin D1; GSK3β/β-catenin pathway; Neural stem cell; Self-renewal; Transcriptional regulation