Journal Article

DZNE-2021-01520

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The transcription factor BCL11A defines distinct subsets of midbrain dopaminergic neurons.

Tolve, M. ; Ulusoy, A.DZNE* ; Patikas, N. ; Islam, K. U. S. ; Bodea, G. O. ; Öztürk, E. ; Broske, B. ; Mentani, A. ; Wagener, A. ; van Loo, K. M. J. ; Britsch, S. ; Liu, P. ; Khaled, W. T. ; Metzakopian, E. ; Baader, S. L. ; Di Monte, D. A.DZNE* ; Blaess, S.

2021
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2021.109697

Abstract: 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.

Keyword(s): Animals (MeSH) ; Behavior, Animal (MeSH) ; Brain: metabolism (MeSH) ; Dopamine: metabolism (MeSH) ; Dopaminergic Neurons: metabolism (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Repressor Proteins: deficiency (MeSH) ; Repressor Proteins: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Substantia Nigra: metabolism (MeSH) ; Substantia Nigra: pathology (MeSH) ; Transcriptome (MeSH) ; Ventral Tegmental Area: metabolism (MeSH) ; Ventral Tegmental Area: pathology (MeSH) ; alpha-Synuclein: genetics (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; alpha-synuclein ; behavior ; circuits ; development ; dopaminergic neurons ; iPSCs ; mouse ; neurodegeneration ; neuronal diversity ; transcription factor

Note: CC BY-NC-ND

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Contributing Institute(s):

1. Neurodegeneration and Neuroprotection in Parkinson´s Disease (AG Di Monte)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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