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      Dmrt5, a Novel Neurogenic Factor, Reciprocally Regulates Lhx2 to Control the Neuron–Glia Cell-Fate Switch in the Developing Hippocampus

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          Abstract

          Regulation of the neuron–glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect. We tested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic Lhx2 overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on Pax6 and Neurog2, indicating a complex bidirectionally regulated network that controls the neuron–glia cell-fate switch.

          SIGNIFICANCE STATEMENT We identify Dmrt5 as a novel regulator of the neuron–glia cell-fate switch in the developing hippocampus. We demonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes Neurog2 and Pax6. Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus.

          Finally, we confirm that Lhx2 binds a highly conserved putative enhancer of Dmrt5, suggesting an evolutionarily conserved regulatory relationship between these factors. Our findings uncover a complex network that involves Lhx2, Dmrt5, Neurog2, and Pax6, and that ensures the appropriate amount and timing of neurogenesis and gliogenesis in the developing hippocampus.

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          Most cited references31

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          Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage.

          By homologous recombination of an internal ribosome entry site and Cre recombinase coding region into the 3'-untranslated region of the mouse Emx1 gene, we have generated a strain of mice, Emx1(IRES)cre, that expresses the Cre recombinase in a spatial and temporal pattern like that observed for Emx1. When mated to reporter strains, these mice are a sensitive means to fate-map the Emx1-expressing cells of the developing forebrain. Our results demonstrate that radial glia, Cajal-Retzius cells, glutamatergic neurons, astrocytes, and oligodendrocytes of most pallial structures originate from an Emx1-expressing lineage. On the other hand, most of the pallial GABAergic neurons arise outside the Emx1-expressing lineage. Structures that are located near the basal ganglia (e.g., the amygdala and endopiriform nuclei) are not uniformly derived from Emx1-expressing cells.
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            Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway.

            A mechanism by which members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor cytokine family regulate gliogenesis in the developing mammalian central nervous system was characterized. Activation of the CNTF receptor promoted differentiation of cerebral cortical precursor cells into astrocytes and inhibited differentiation of cortical precursors along a neuronal lineage. Although CNTF stimulated both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Ras-mitogen-activated protein kinase signaling pathways in cortical precursor cells, the JAK-STAT signaling pathway selectively enhanced differentiation of these precursors along a glial lineage. These findings suggest that cytokine activation of the JAK-STAT signaling pathway may be a mechanism by which cell fate is controlled during mammalian development.
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              Timing is everything: making neurons versus glia in the developing cortex.

              During development of the mammalian nervous system, neural stem cells generate neurons first and glia second, thereby allowing the initial establishment of neural circuitry, and subsequent matching of glial numbers and position to that circuitry. Here, we have reviewed work addressing the mechanisms underlying this timed cell genesis, with a particular focus on the developing cortex. These studies have defined an intriguing interplay between intrinsic epigenetic status, transcription factors, and environmental cues, all of which work together to establish this fascinating and complex biological timing mechanism.
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                Author and article information

                Journal
                J Neurosci
                J. Neurosci
                jneuro
                jneurosci
                J. Neurosci
                The Journal of Neuroscience
                Society for Neuroscience
                0270-6474
                1529-2401
                15 November 2017
                15 November 2017
                : 37
                : 46
                : 11245-11254
                Affiliations
                [1] 1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400 005, India,
                [2] 2Université Libre de Bruxelles (ULB), ULB Institute of Neuroscience, B-6041 Gosselies, Belgium,
                [3] 3Centre of Excellence in Epigenetics, Indian Institute of Science, Education and Research, Pune 411 008, India, and
                [4] 4Department of Life Sciences, Sophia College for Women, Mumbai 400 026, India
                Author notes
                Correspondence should be addressed to either of the following: Eric J. Bellefroid or Shubha Tole. ebellefr@ 123456ulb.ac.be or shubhatole@ 123456gmail.com

                Author contributions: B.M., S.J.P., A.S.S., V.K., U.M., S.G., E.J.B., and S.T. designed research; B.M., M.K., S.J.P., B.R., A.S.S., V.K., L.D., U.M., and A.S. performed research; B.M., M.K., A.S.S., V.K., U.M., K.K., S.G., E.J.B., and S.T. analyzed data; B.M. and S.T. wrote the paper.

                Author information
                http://orcid.org/0000-0003-1184-0833
                http://orcid.org/0000-0002-5306-9138
                http://orcid.org/0000-0002-5089-5151
                http://orcid.org/0000-0002-9206-4815
                http://orcid.org/0000-0001-9681-2369
                http://orcid.org/0000-0002-7251-1905
                http://orcid.org/0000-0001-6584-443X
                Article
                1535-17
                10.1523/JNEUROSCI.1535-17.2017
                5688529
                29025924
                15809300-acf0-44e7-be1d-b383b07f7065
                Copyright © 2017 Muralidharan et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 1 June 2017
                : 18 September 2017
                : 23 September 2017
                Categories
                Research Articles
                Development/Plasticity/Repair

                cell fate,glia,hippocampus,neuron
                cell fate, glia, hippocampus, neuron

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