The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons.
Animals
Behavior, Animal
Brain
/ metabolism
Dopamine
/ metabolism
Dopaminergic Neurons
/ metabolism
Humans
Induced Pluripotent Stem Cells
/ cytology
Male
Mice
Mice, Knockout
Repressor Proteins
/ deficiency
Substantia Nigra
/ metabolism
Transcriptome
Ventral Tegmental Area
/ metabolism
alpha-Synuclein
/ genetics
alpha-synuclein
behavior
circuits
development
dopaminergic neurons
iPSCs
mouse
neurodegeneration
neuronal diversity
transcription factor
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
received:
13
03
2021
revised:
08
07
2021
accepted:
18
08
2021
entrez:
15
9
2021
pubmed:
16
9
2021
medline:
16
2
2022
Statut:
ppublish
Résumé
Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, effect on behavior, and susceptibility to neurodegeneration. Little is known about the molecular mechanisms establishing this diversity during development. We show that the transcription factor BCL11A is expressed in a subset of mDA neurons in the developing and adult murine brain and in a subpopulation of pluripotent-stem-cell-derived human mDA neurons. By combining intersectional labeling and viral-mediated tracing, we demonstrate that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the murine dopaminergic system. In the substantia nigra, the Bcl11a-expressing mDA subset is particularly vulnerable to neurodegeneration upon α-synuclein overexpression or oxidative stress. Inactivation of Bcl11a in murine mDA neurons increases this susceptibility further, alters the distribution of mDA neurons, and results in deficits in skilled motor behavior. In summary, BCL11A defines mDA subpopulations with highly distinctive characteristics and is required for establishing and maintaining their normal physiology.
Identifiants
pubmed: 34525371
pii: S2211-1247(21)01144-X
doi: 10.1016/j.celrep.2021.109697
pii:
doi:
Substances chimiques
Bcl11a protein, mouse
0
Repressor Proteins
0
alpha-Synuclein
0
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109697Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.