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

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Date
2017
Authors
Hegarty, Shane V.
Wyatt, Sean L.
Howard, Laura
Stappers, Elke
Huylebroeck, Danny
Sullivan, Aideen M.
O'Keeffe, Gerard W.
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Nature Publishing Group
Published Version
10.1038/s41598-017-08900-3
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Abstract
Neural 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.
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Keywords
Neurons in vitro , Schwann cell differentiation , Nervous system development , Parkinsons disease , Neurite growth , Factor beta , Sip1 , Morphology , Repressor , Survival
Citation
Hegarty, 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/s41598-017-08900-3
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https://www.nature.com/articles/s41598-017-08900-3
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https://hdl.handle.net/10468/4805
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Anatomy and Neuroscience - Journal Articles
APC Microbiome Ireland - Journal Articles
INFANT Research Centre - Journal Articles
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© 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.