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TitleTranscriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation.
Publication TypeJournal Article
Year of Publication2017
AuthorsChabrat, Audrey, Guillaume Brisson, Hélène Doucet-Beaupré, Charleen Salesse, Marcos Schaan Profes, Axelle Dovonou, Cléophace Akitegetse, Julien Charest, Suzanne Lemstra, Daniel Côté, Jeroen R Pasterkamp, Monica I. Abrudan, Emmanouil Metzakopian, Siew-Lan Ang, and Martin Lévesque
JournalNat Commun
Date Published2017 10 16
KeywordsAnimals, Antigens, CD, Axons, Dopaminergic Neurons, Female, Gene Expression Regulation, LIM-Homeodomain Proteins, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Nerve Tissue Proteins, Otx Transcription Factors, Receptors, Cell Surface, Semaphorins, Transcription Factors, Ventral Tegmental Area

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.Midbrain dopaminergic neurons (mDAs) in the VTA and SNpc project to different regions and form distinct circuits. Here the authors show that transcription factors Lmx1a, Lmx1b, and Otx2 control the axon guidance of mDAs and the segregation of mesolimbic and nigrostriatal dopaminergic pathways.

Alternate JournalNat Commun
PubMed ID29038581
PubMed Central IDPMC5643336
Grant List / / Wellcome Trust / United Kingdom
G-0906 / / Parkinson's UK / United Kingdom