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EMBO J. 2016 Sep 15;35(18):1963-78. doi: 10.15252/embj.201593725. Epub 2016 Jun 28.

A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease.

Author information

1
Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic Psychiatric Stem Cell Group, Neurogenetics Unit, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
2
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.
3
Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4
John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
5
Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
6
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden.
7
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
8
Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ernest.arenas@ki.se.

Abstract

Pre-B-cell leukemia homeobox (PBX) transcription factors are known to regulate organogenesis, but their molecular targets and function in midbrain dopaminergic neurons (mDAn) as well as their role in neurodegenerative diseases are unknown. Here, we show that PBX1 controls a novel transcriptional network required for mDAn specification and survival, which is sufficient to generate mDAn from human stem cells. Mechanistically, PBX1 plays a dual role in transcription by directly repressing or activating genes, such as Onecut2 to inhibit lateral fates during embryogenesis, Pitx3 to promote mDAn development, and Nfe2l1 to protect from oxidative stress. Notably, PBX1 and NFE2L1 levels are severely reduced in dopaminergic neurons of the substantia nigra of Parkinson's disease (PD) patients and decreased NFE2L1 levels increases damage by oxidative stress in human midbrain cells. Thus, our results reveal novel roles for PBX1 and its transcriptional network in mDAn development and PD, opening the door for new therapeutic interventions.

KEYWORDS:

ChIP‐Seq; dopamine; dopaminergic differentiation; mesencephalon; stem cells

PMID:
27354364
PMCID:
PMC5282836
DOI:
10.15252/embj.201593725
[Indexed for MEDLINE]
Free PMC Article

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