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      Taurine Induces Proliferation of Neural Stem Cells and Synapse Development in the Developing Mouse Brain

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          Abstract

          Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC) proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5) hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems.

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          Most cited references40

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          GAP-43: an intrinsic determinant of neuronal development and plasticity.

          Several lines of investigation have helped clarify the role of GAP-43 (FI, B-50 or neuromodulin) in regulating the growth state of axon terminals. In transgenic mice, overexpression of GAP-43 leads to the spontaneous formation of new synapses and enhanced sprouting after injury. Null mutation of the GAP-43 gene disrupts axonal pathfinding and is generally lethal shortly after birth. Manipulations of GAP-43 expression likewise have profound effects on neurite outgrowth for cells in culture. GAP-43 appears to be involved in transducing intra- and extracellular signals to regulate cytoskeletal organization in the nerve ending. Phosphorylation by protein kinase C is particularly significant in this regard, and is linked with both nerve-terminal sprouting and long-term potentiation. In the brains of humans and other primates, high levels of GAP-43 persist in neocortical association areas and in the limbic system throughout life, where the protein might play an important role in mediating experience-dependent plasticity.
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            Neurons born in the adult dentate gyrus form functional synapses with target cells.

            Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent studies have demonstrated that newborn granule cells of the adult hippocampus are postsynaptic targets of excitatory and inhibitory neurons, but evidence of synapse formation by the axons of these cells is still lacking. By combining retroviral expression of green fluorescent protein in adult-born neurons of the mouse dentate gyrus with immuno-electron microscopy, we found output synapses that were formed by labeled terminals on appropriate target cells in the CA3 area and the hilus. Furthermore, retroviral expression of channelrhodopsin-2 allowed us to light-stimulate newborn granule cells and identify postsynaptic target neurons by whole-cell recordings in acute slices. Our structural and functional evidence indicates that axons of adult-born granule cells establish synapses with hilar interneurons, mossy cells and CA3 pyramidal cells and release glutamate as their main neurotransmitter.
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              JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.

              The roles of the JAK/STAT, Raf/MEK/ERK and PI3K/Akt signal transduction pathways and the BCR-ABL oncoprotein in leukemogenesis and their importance in the regulation of cell cycle progression and apoptosis are discussed in this review. These pathways have evolved regulatory proteins, which serve to limit their proliferative and antiapoptotic effects. Small molecular weight cell membrane-permeable drugs that target these pathways have been developed for leukemia therapy. One such example is imatinib mesylate, which targets the BCR-ABL kinase as well as a few structurally related kinases. This drug has proven to be effective in the treatment of CML patients. However, leukemic cells have evolved mechanisms to become resistant to this drug. A means to combat drug resistance is to target other prominent signaling components involved in the pathway or to inhibit BCR-ABL by other mechanisms. Treatment of imatinib-resistant leukemia cells with drugs that target Ras (farnysyl transferase inhibitors) or with the protein destabilizer geldanamycin has proven to be a means to inhibit the growth of resistant cells. This review will tie together three important signal transduction pathways involved in the regulation of hematopoietic cell growth and indicate how their expression is dysregulated by the BCR-ABL oncoprotein.
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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
                2012
                20 August 2012
                : 7
                : 8
                : e42935
                Affiliations
                [1 ]Program in Neuroscience and Behavioral Disorder, Duke-NUS Graduate Medical School, Singapore, Singapore
                [2 ]Cognition Center of Excellence, Abbott Nutrition Research & Development, Asia Pacific Center, Singapore, Singapore
                [3 ]Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
                [4 ]A*STAR-Duke-NUS Neuroscience Research Partnership, Proteos, Singapore, Singapore
                University of Texas Health Science Center at San Antonio, United States of America
                Author notes

                Competing Interests: The authors have read the journal’s policy and have the following conflicts: EG is consultant for and FR and XZ are employees of Abbott Nutrition Research & Development. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: EG MCS FJR XZ. Performed the experiments: MCS GL GM JRR. Analyzed the data: MCS GL GM EG. Contributed reagents/materials/analysis tools: FJR XZ. Wrote the paper: EG MCS FJR.

                Article
                PONE-D-12-00805
                10.1371/journal.pone.0042935
                3423436
                22916184
                8019db47-d975-4587-845c-eba7c0db858f
                Copyright @ 2012

                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
                : 5 January 2012
                : 15 July 2012
                Page count
                Pages: 12
                Funding
                The present research is supported by: A Startup fund from Duke-NUS Graduate Medical School, Singapore 169857 and Abbott Nutrition Research & Development, Singapore 138668. The funders had no role in study design, data collection, decision to publish and analysis or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Neurological System
                Neuroanatomy
                Developmental Biology
                Stem Cells
                Neural Stem Cells
                Model Organisms
                Animal Models
                Mouse
                Neuroscience
                Cellular Neuroscience
                Developmental Neuroscience
                Molecular Neuroscience
                Neural Networks

                Uncategorized
                Uncategorized

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