Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation

Audrey Chabrat, Guillaume Brisson, Hélène Doucet-Beaupré, Charleen Salesse, Marcos Schaan Profes, Axelle Dovonou, Cléophace Akitegetse, Julien Charest, Suzanne Lemstra, Daniel Côté, R. Jeroen Pasterkamp, Monica I. Abrudan, Emmanouil Metzakopian, Siew-Lan Ang and Martin Lévesque ()
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Audrey Chabrat: Université Laval
Guillaume Brisson: Université Laval
Hélène Doucet-Beaupré: Université Laval
Charleen Salesse: Université Laval
Marcos Schaan Profes: Université Laval
Axelle Dovonou: Université Laval
Cléophace Akitegetse: Université Laval
Julien Charest: Université Laval
Suzanne Lemstra: University Medical Center Utrecht
Daniel Côté: chemin de la Canardière
R. Jeroen Pasterkamp: University Medical Center Utrecht
Monica I. Abrudan: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Emmanouil Metzakopian: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
Siew-Lan Ang: The Francis Crick Institute
Martin Lévesque: Université Laval

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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, 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.

Date: 2017
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DOI: 10.1038/s41467-017-01042-0

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