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      Radmis, a Novel Mitotic Spindle Protein that Functions in Cell Division of Neural Progenitors

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          Abstract

          Developmental dynamics of neural stem/progenitor cells (NSPCs) are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis ( radial fiber and mitotic spindle )/ckap2l gene, a novel microtubule-associated protein (MAP) enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C), and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs.

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          CNS stem cells express a new class of intermediate filament protein.

          Multipotential CNS stem cells receive and implement instructions governing differentiation to diverse neuronal and glial fates. Exploration of the mechanisms generating the many cell types of the brain depends crucially on markers identifying the stem cell state. We describe a gene whose expression distinguishes the stem cells from the more differentiated cells in the neural tube. This gene was named nestin because it is specifically expressed in neuroepithelial stem cells. The predicted amino acid sequence of the nestin gene product shows that nestin defines a distinct sixth class of intermediate filament protein. These observations extend a model in which transitions in intermediate filament gene expression reflect major steps in the pathway of neural differentiation.
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            Subventricular zone astrocytes are neural stem cells in the adult mammalian brain.

            Neural stem cells reside in the subventricular zone (SVZ) of the adult mammalian brain. This germinal region, which continually generates new neurons destined for the olfactory bulb, is composed of four cell types: migrating neuroblasts, immature precursors, astrocytes, and ependymal cells. Here we show that SVZ astrocytes, and not ependymal cells, remain labeled with proliferation markers after long survivals in adult mice. After elimination of immature precursors and neuroblasts by an antimitotic treatment, SVZ astrocytes divide to generate immature precursors and neuroblasts. Furthermore, in untreated mice, SVZ astrocytes specifically infected with a retrovirus give rise to new neurons in the olfactory bulb. Finally, we show that SVZ astrocytes give rise to cells that grow into multipotent neurospheres in vitro. We conclude that SVZ astrocytes act as neural stem cells in both the normal and regenerating brain.
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              Astrocytes give rise to new neurons in the adult mammalian hippocampus.

              Neurogenesis in the dentate gyrus of the hippocampus persists throughout life in many vertebrates, including humans. The progenitors of these new neurons reside in the subgranular layer (SGL) of the dentate gyrus. Although stem cells that can self-renew and generate new neurons and glia have been cultured from the adult mammalian hippocampus, the in vivo primary precursors for the formation of new neurons have not been identified. Here we show that SGL cells, which express glial fibrillary acidic protein and have the characteristics of astrocytes, divide and generate new neurons under normal conditions or after the chemical removal of actively dividing cells. We also describe a population of small electron-dense SGL cells, which we call type D cells and are derived from the astrocytes and probably function as a transient precursor in the formation of new neurons. These results reveal the origins of new neurons in the adult hippocampus.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                8 November 2013
                : 8
                : 11
                : e79895
                Affiliations
                [1 ]Laboratory for Molecular Neurobiology, Graduate School of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan
                [2 ]Department of Basic Biology, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, Kiyose-shi, Tokyo, Japan
                [3 ]Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan
                [4 ]RIKEN Brain Science Institute, Wako, Saitama, Japan
                [5 ]Department of Molecular Immunology and Inflammation, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
                [6 ]Department of Histology and Neurobiology, Graduate School of Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan
                [7 ]Institute of Applied Brain Sciences, Waseda University, Tokorozawa, Saitama, Japan
                University of Queensland, Australia
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SS. Performed the experiments: TY KN YN SS. Analyzed the data: KN YS SU YN SS. Contributed reagents/materials/analysis tools: RSY YS. Wrote the manuscript: TY SS.

                Article
                PONE-D-13-32739
                10.1371/journal.pone.0079895
                3832648
                24260314
                47fc7183-0152-47a6-8a5d-9f32ce59631d
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 August 2013
                : 26 September 2013
                Funding
                This work was supported by JSPS KAKENHI to SS (Grant numbers 20590196 and 17590173) and partially by a Waseda University Grant for Special Research Projects (Grant number 2011B-260) and MEXT KIBANKEISEI (2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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