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      Ascl1 (Mash1) Defines Cells with Long-Term Neurogenic Potential in Subgranular and Subventricular Zones in Adult Mouse Brain

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          Abstract

          Ascl1 (Mash1) is a bHLH transcription factor essential for neural differentiation during embryogenesis but its role in adult neurogenesis is less clear. Here we show that in the adult brain Ascl1 is dynamically expressed during neurogenesis in the dentate gyrus subgranular zone (SGZ) and more rostral subventricular zone (SVZ). Specifically, we find Ascl1 levels low in SGZ Type-1 cells and SVZ B cells but increasing as the cells transition to intermediate progenitor stages. In vivo genetic lineage tracing with a tamoxifen (TAM) inducible Ascl1 CreERT2 knock-in mouse strain shows that Ascl1 lineage cells continuously generate new neurons over extended periods of time. There is a regionally-specific difference in neuron generation, with mice given TAM at postnatal day 50 showing new dentate gyrus neurons through 30 days post-TAM, but showing new olfactory bulb neurons even 180 days post-TAM. These results show that Ascl1 is not restricted to transit amplifying populations but is also found in a subset of neural stem cells with long-term neurogenic potential in the adult brain.

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          Most cited references18

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          Direct conversion of fibroblasts to functional neurons by defined factors

          Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2, and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modeling, and regenerative medicine.
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            Milestones of neuronal development in the adult hippocampus.

            Adult hippocampal neurogenesis originates from precursor cells in the adult dentate gyrus and results in new granule cell neurons. We propose a model of the development that takes place between these two fixed points and identify several developmental milestones. From a presumably bipotent radial-glia-like stem cell (type-1 cell) with astrocytic properties, development progresses over at least two stages of amplifying lineage-determined progenitor cells (type-2 and type-3 cells) to early postmitotic and to mature neurons. The selection process, during which new neurons are recruited into function, and other regulatory influences differentially affect the different stages of development.
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              Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging.

              New neurons are generated in the adult hippocampus throughout life by neural stem/progenitor cells (NSCs), and neurogenesis is a plastic process responsive to external stimuli. We show that canonical Notch signaling through RBP-J is required for hippocampal neurogenesis. Notch signaling distinguishes morphologically distinct Sox2(+) NSCs, and within these pools subpopulations can shuttle between mitotically active or quiescent. Radial and horizontal NSCs respond selectively to neurogenic stimuli. Physical exercise activates the quiescent radial population whereas epileptic seizures induce expansion of the horizontal NSC pool. Surprisingly, reduced neurogenesis correlates with a loss of active horizontal NSCs in aged mice rather than a total loss of stem cells, and the transition to a quiescent state is reversible to rejuvenate neurogenesis in the brain. The discovery of multiple NSC populations with Notch dependence but selective responses to stimuli and reversible quiescence has important implications for the mechanisms of adaptive learning and also for regenerative therapy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                31 March 2011
                01 April 2011
                : 6
                : 3
                : e18472
                Affiliations
                [1 ]Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                [2 ]Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
                Institut de la Vision, France
                Author notes

                Conceived and designed the experiments: EJK JLA AJE JEJ. Performed the experiments: EJK JLA LKD. Analyzed the data: EJK JLA. Contributed reagents/materials/analysis tools: AJE JEJ. Wrote the paper: EJK JEJ.

                Article
                PONE-D-11-01383
                10.1371/journal.pone.0018472
                3069117
                21483754
                ae07078b-4efe-4b39-b56b-7e408ed57e04
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                History
                : 12 January 2011
                : 2 March 2011
                Page count
                Pages: 6
                Categories
                Research Article
                Biology
                Developmental Biology
                Stem Cells
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Cellular Types
                Neurons
                Gene Expression
                DNA transcription
                Neuroscience
                Developmental Neuroscience

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                Uncategorized

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