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      E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner

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          Abstract

          Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins’ activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their preferential binding to CADATG motifs. Since we find this mechanism to be conserved in corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a novel though general feature of their mechanism of action.

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          The brain and spinal cord are made up of a range of cell types that carry out different roles within the central nervous system. Each type of neuron is uniquely specialized to do its job. Neurons are produced early during development, when they differentiate from a group of cells called neural progenitor cells. Within these groups, molecules called proneural proteins control which types of neurons will develop from the neural progenitor cells, and how many of them.

          Proneural proteins work by binding to specific patterns in the DNA, called E-boxes, with the help of E proteins. E proteins are typically understood to be passive partners, working with each different proneural protein indiscriminately. However, Le Dréau, Escalona et al. discovered that E proteins in fact have a much more active role to play.

          Using chick embryos, it was found that E proteins influence the way different proneural proteins bind to DNA. The E proteins have preferences for certain E-boxes in the DNA, just like proneural proteins do. The E proteins enhanced the activity of the proneural proteins that share their E-box preference, and reined in the activity of proneural proteins that prefer other E-boxes. As a result, the E proteins controlled the ability of these proteins to instruct neural progenitor cells to produce specific, specialized neurons, and thus ensured that the distinct types of neurons were produced in appropriate amounts.

          These findings will help shed light on the roles E proteins play in the development of the central nervous system, and the processes that control growth and lead to cell diversity. The results may also have applications in the field of regenerative medicine, as proneural proteins play an important role in cell reprogramming.

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          Most cited references50

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          A series of normal stages in the development of the chick embryo

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            A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins.

            Two cDNAs were isolated whose dimerized products bind specifically to a DNA sequence, kappa E2, located in the immunoglobulin kappa chain enhancer. Both cDNAs share a region of extensive identity to the Drosophila daughterless gene and obvious similarity to a segment in three myc proteins, MyoD, and members of the Drosophila achaete-scute and twist gene family. The homologous regions have the potential to form two amphipathic helices separated by an intervening loop. Remarkable is the stringent conservation of hydrophobic residues present in both helices. We demonstrate that this new motif plays a crucial role in both dimerization and DNA binding.
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              Helix-Loop-Helix Proteins: Regulators of Transcription in Eucaryotic Organisms

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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                10 August 2018
                2018
                : 7
                : e37267
                Affiliations
                [1 ]deptDepartment of Developmental Biology Instituto de Biología Molecular de Barcelona BarcelonaSpain
                [2 ]deptDepartment of Molecular Genomics Instituto de Biología Molecular de Barcelona BarcelonaSpain
                [3 ]deptDepartment of Cell Biology Instituto de Biología Molecular de Barcelona BarcelonaSpain
                Johns Hopkins University School of Medicine United States
                California Institute of Technology United States
                Johns Hopkins University School of Medicine United States
                Author notes
                [‡]

                Departamento de Embriología, Facultad de Medicina, Universidad Nacional Autónoma de México, México City, Mexico.

                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-6877-3670
                http://orcid.org/0000-0001-7106-7163
                https://orcid.org/0000-0001-5839-7133
                Article
                37267
                10.7554/eLife.37267
                6126921
                30095408
                e92cf118-37bf-4f01-ae39-3f84d83fb871
                © 2018, Le Dréau et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 05 April 2018
                : 09 August 2018
                Funding
                Funded by: Asociación Española Contra el Cáncer;
                Award ID: AIO2014
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003141, Consejo Nacional de Ciencia y Tecnología;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003176, Ministerio de Educación, Cultura y Deporte;
                Award ID: #FPU13/01384
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: #FJCI-2015-26175
                Award Recipient :
                Funded by: Ministerio de Economía y Competitividad;
                Award ID: BFU2014-53633-P
                Award Recipient :
                Funded by: Ministerio de Economía y Competitividad;
                Award ID: BFU2015-69248-P
                Award Recipient :
                Funded by: Fondation Jérôme Lejeune;
                Award ID: Fondation Jérôme Lejeune.2016
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: BFU2016-81887-REDT
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: BFU2016-77498-P
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Developmental Biology
                Custom metadata
                Rather than acting as passive and neutral co-factors for proneural proteins, E proteins play an active role in modulating the way the distinct proneural proteins instruct neurogenesis.

                Life sciences
                e proteins,proneural proteins,neurogenesis,neuronal differentiation,id proteins,bone morphogenetic proteins,chicken

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