title: A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease.
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.
authors.affiliation: 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.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Villaescusa
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Bingsi
authors.initials: B
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Toledo
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Rivetti di Val Cervo
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Shanzheng
authors.initials: S
authors.lastname: Yang
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Simon Rw
authors.initials: SR
authors.lastname: Stott
authors.affiliation: 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.
authors.forename: Karol
authors.initials: K
authors.lastname: Kaiser
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Saiful
authors.initials: S
authors.lastname: Islam
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gyllborg
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Rocio
authors.initials: R
authors.lastname: Laguna-Goya
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Landreh
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Lönnerberg
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Falk
authors.affiliation: Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Bergman
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.affiliation: Laboratory of Molecular Neurobiology, DBRM, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ernest.arenas@ki.se.
authors.forename: Ernest
authors.identifier: 0000-0003-0197-6577
authors.initials: E
authors.lastname: Arenas
mesh_terms: D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000502:physiology*; D053263:Gene Regulatory Networks; D006801:Humans; D010300:Parkinson Disease / Q000473:pathology*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human
keywords: ChIP‐Seq; dopamine; dopaminergic differentiation; mesencephalon; stem cells