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      Pluripotent Stem Cells for the Study of CNS Development

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          Abstract

          The mammalian central nervous system is a complex neuronal network consisting of a diverse array of cellular subtypes generated in a precise spatial and temporal pattern throughout development. Achieving a greater understanding of the molecular and genetic mechanisms that direct a relatively uniform population of neuroepithelial progenitors into diverse neuronal subtypes remains a significant challenge. The advent of pluripotent stem cell (PSC) technology allows researchers to generate diverse neural populations in vitro. Although the primary focus of PSC-derived neural cells has been their therapeutic potential, utilizing PSCs to study neurodevelopment is another frequently overlooked and equally important application. In this review, we explore the potential for utilizing PSCs to study neural development. We introduce the types of neurodevelopmental questions that PSCs can help to address, and we discuss the different strategies and technologies that researchers use to generate diverse subtypes of PSC-derived neurons. Additionally, we highlight the derivation of several thoroughly characterized neural subtypes; spinal motoneurons, midbrain dopaminergic neurons and cortical neurons. We hope that this review encourages researchers to develop innovative strategies for using PSCs for the study of mammalian, and specifically human, neurodevelopment.

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          Most cited references76

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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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            Mechanisms and functional implications of adult neurogenesis.

            The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. In this review, we discuss the factors that regulate proliferation and fate determination of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
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              Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

              G Martin (1981)
              This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.
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                Author and article information

                Journal
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Research Foundation
                1662-5099
                12 October 2011
                2011
                : 4
                : 30
                Affiliations
                [1] 1simpleDepartment of Psychiatry, Weill Cornell Medical College New York, NY, USA
                [2] 2simpleProgram in Neuroscience, Weill Cornell Medical College New York, NY, USA
                Author notes

                Edited by: Alistair N. Garratt, Max Delbrück Center for Molecular Medicine, Germany

                Reviewed by: Ye He, University of California San Francisco, USA; Smita Jha, Baylor College of Medicine, USA

                *Correspondence: Stewart A. Anderson, Department of Psychiatry, Weill Cornell Medical College, Box 244, 1300 York Avenue, New York, NY 10065, USA. e-mail: saa2007@ 123456med.cornell.edu

                This article was submitted to Frontiers in Molecular Neuroscience, a specialty of Frontiers in Molecular Neuroscience.

                Article
                10.3389/fnmol.2011.00030
                3191505
                22016722
                fb595c70-387e-460d-8f1d-4e9d02f6f069
                Copyright © 2011 Petros, Tyson and Anderson.

                This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

                History
                : 05 July 2011
                : 23 September 2011
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 109, Pages: 12, Words: 11313
                Categories
                Neuroscience
                Review Article

                Neurosciences
                neurons,development,derivation,embryonic,nervous system,pluripotent,stem cells
                Neurosciences
                neurons, development, derivation, embryonic, nervous system, pluripotent, stem cells

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