Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation
Chabrat, Audrey; Brisson, Guillaume; Doucet-Beaupré, Hélène; Salesse, Charleen; Schaan Profes, Marcos; Dovonou, Axelle; Akitegetse, Cléophace; Charest, Julien; Lemstra, Suzanne; Côté, Daniel; Pasterkamp, R. Jeroen; Abrudan, Monica I.; Metzakopian, Emmanouil; Ang, Siew Lan; Lévesque, Martin
(2017) Nature Communications [E], volume 8, issue 1
(Article)
Abstract
Mesodiencephalic dopamine neurons play central roles in the regulation of a wide range of brain functions, including voluntary movement and behavioral processes. These functions are served by distinct subtypes of mesodiencephalic dopamine neurons located in the substantia nigra pars compacta and the ventral tegmental area, which form the nigrostriatal, mesolimbic,
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and mesocortical pathways. Until now, mechanisms involved in dopaminergic circuit formation remained largely unknown. Here, we show that Lmx1a, Lmx1b, and Otx2 transcription factors control subtype-specific mesodiencephalic dopamine neurons and their appropriate axon innervation. Our results revealed that the expression of Plxnc1, an axon guidance receptor, is repressed by Lmx1a/b and enhanced by Otx2. We also found that Sema7a/Plxnc1 interactions are responsible for the segregation of nigrostriatal and mesolimbic dopaminergic pathways. These findings identify Lmx1a/b, Otx2, and Plxnc1 as determinants of dopaminergic circuit formation and should assist in engineering mesodiencephalic dopamine neurons capable of regenerating appropriate connections for cell therapy.
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Keywords: Axon and dendritic guidance, Neuroscience, Cell type diversity, General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: This work was mainly supported by a grant from the Natural Sciences and Engineering Research Council of Canada (NSERC: 418391-2012) and by Canadian Institutes of Health Research Grants MOP 311120 to M.L. A.C. received a scholarship from the Fondation de l’institut universitaire en santé mentale de Québec, and from the Centre thématique de recherche en neurosciences (CTRN). M.L. is a FRSQ Chercheur-Boursier. R.J.P. received funding from Stichting ParkinsonFonds and the Netherlands Organization for Scientific Research (ALW-VICI). S.-L.A. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001089), the UK Medical Research Council (FC001089), and the Wellcome Trust (FC001089); and by Parkinson’s UK research grant G0617. E.M. is funded by Parkinson’s Disease UK (F1501). We thank Veronique Rioux for technical assistance. We thank Meng Li for sharing Pitx3-GFP mice and Thomas Perlmann for Lmx1a flox mice. We thank Dr Armen Saghatelyan for his useful comments and Dr Louis-Eric Trudeau for sharing Sema7a KO mice. We also thank the Plateforme d’Outils Moléculaires (https://www. neurophotonics.ca/fr/pom) for the production of the viral vectors used in this study. Publisher Copyright: © 2017 The Author(s).
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