Format

Send to

Choose Destination
Nat Commun. 2017 Oct 16;8(1):933. doi: 10.1038/s41467-017-01042-0.

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

Author information

1
Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Québec, Quebec, G1V 0A6, Canada.
2
CERVO Brain Research Centre, 2601, chemin de la Canardière, Québec, Quebec, Canada, G1J 2G3.
3
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
4
Département de Physique, Genie Physique et Optique, Université Laval, Québec, Quebec, G1V 0A6, Canada.
5
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
6
Faculty of Medicine, School of Public Health, Imperial College, London, W2 1PG, UK.
7
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
8
Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Québec, Quebec, G1V 0A6, Canada. martin.levesque@fmed.ulaval.ca.
9
CERVO Brain Research Centre, 2601, chemin de la Canardière, Québec, Quebec, Canada, G1J 2G3. martin.levesque@fmed.ulaval.ca.

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.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.

PMID:
29038581
PMCID:
PMC5643336
DOI:
10.1038/s41467-017-01042-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center