Zeb2 is a negative regulator of midbrain dopaminergic axon growth and target innervation

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dc.contributor.authorHegarty, Shane V.
dc.contributor.authorWyatt, Sean L.
dc.contributor.authorHoward, Laura
dc.contributor.authorStappers, Elke
dc.contributor.authorHuylebroeck, Danny
dc.contributor.authorSullivan, Aideen M.
dc.contributor.authorO'Keeffe, Gerard W.
dc.contributor.funderIrish Research Council
dc.contributor.funderRoyal Irish Academy
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderFonds Wetenschappelijk Onderzoek
dc.contributor.funderFederaal Wetenschapsbeleid
dc.contributor.funderErasmus Medisch Centrum
dc.date.accessioned2017-09-26T11:39:23Z
dc.date.available2017-09-26T11:39:23Z
dc.date.issued2017
dc.description.abstractNeural connectivity requires neuronal differentiation, axon growth, and precise target innervation. Midbrain dopaminergic neurons project via the nigrostriatal pathway to the striatum to regulate voluntary movement. While the specification and differentiation of these neurons have been extensively studied, the molecular mechanisms that regulate midbrain dopaminergic axon growth and target innervation are less clear. Here we show that the transcription factor Zeb2 cell-autonomously represses Smad signalling to limit midbrain dopaminergic axon growth and target innervation. Zeb2 levels are downregulated in the embryonic rodent midbrain during the period of dopaminergic axon growth, when BMP pathway components are upregulated. Experimental knockdown of Zeb2 leads to an increase in BMP-Smad-dependent axon growth. Consequently there is dopaminergic hyperinnervation of the striatum, without an increase in the numbers of midbrain dopaminergic neurons, in conditional Zeb2 (Nestin-Cre based) knockout mice. Therefore, these findings reveal a new mechanism for the regulation of midbrain dopaminergic axon growth during central nervous system development.en
dc.description.sponsorshipFonds Wetenschappelijk Onderzoek (FWO-VG.0782.14); Federaal Wetenschapsbeleid (Belspo) (IAP7-07 DevRepair)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid8568
dc.identifier.citationHegarty, S. V., Wyatt, S. L., Howard, L., Stappers, E., Huylebroeck, D., Sullivan, A. M. and O’Keeffe, G. W. (2017) 'Zeb2 is a negative regulator of midbrain dopaminergic axon growth and target innervation', Scientific Reports, 7(1), 8568 (11pp). doi: 10.1038/s41598-017-08900-3en
dc.identifier.doi10.1038/s41598-017-08900-3
dc.identifier.issn2045-2322
dc.identifier.journaltitleScientific Reportsen
dc.identifier.urihttps://hdl.handle.net/10468/4805
dc.identifier.volume7
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Career Development Award/15/CDA/3498/IE/Development of GDF5 neurotrophic factor therapy for Parkinson_s disease./
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2272/IE/Irish Centre for Fetal and Neonatal Translational Research (INFANT)/
dc.relation.urihttps://www.nature.com/articles/s41598-017-08900-3
dc.rights© 2017, the Authors. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectNeurons in vitroen
dc.subjectSchwann cell differentiationen
dc.subjectNervous system developmenten
dc.subjectParkinsons diseaseen
dc.subjectNeurite growthen
dc.subjectFactor betaen
dc.subjectSip1en
dc.subjectMorphologyen
dc.subjectRepressoren
dc.subjectSurvivalen
dc.titleZeb2 is a negative regulator of midbrain dopaminergic axon growth and target innervationen
dc.typeArticle (peer-reviewed)en
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