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

Villaescusa, J Carlos ; Li, Bingsi ; Toledo, Enrique M ; Rivetti di Val Cervo, Pia ; Yang, Shanzheng ; Stott, Simon RW ; Kaiser, Karol ; Islam, Saiful ; Gyllborg, Daniel ; Laguna-Goya, Rocio ; Landreh, Michael ; Lönnerberg, Peter ; Falk, Anna ; Bergman, Tomas ; Barker, Roger A ; Linnarsson, Sten ; Selleri, Licia ; Arenas, Ernest

The EMBO journal, 2016-09, Vol.35 (18), p.1963-1978 [Periódico revisado por pares]

England: Blackwell Publishing Ltd

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  • Título:
    A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease
  • Autor: Villaescusa, J Carlos ; Li, Bingsi ; Toledo, Enrique M ; Rivetti di Val Cervo, Pia ; Yang, Shanzheng ; Stott, Simon RW ; Kaiser, Karol ; Islam, Saiful ; Gyllborg, Daniel ; Laguna-Goya, Rocio ; Landreh, Michael ; Lönnerberg, Peter ; Falk, Anna ; Bergman, Tomas ; Barker, Roger A ; Linnarsson, Sten ; Selleri, Licia ; Arenas, Ernest
  • Assuntos: Cell Differentiation ; ChIP-Seq ; DNA-Binding Proteins - metabolism ; dopamine ; dopaminergic differentiation ; Dopaminergic Neurons - physiology ; Gene Regulatory Networks ; Humans ; Medicin och hälsovetenskap ; mesencephalon ; Neurons ; Oxidative stress ; Parkinson Disease - pathology ; Parkinsons disease ; Pre-B-Cell Leukemia Transcription Factor 1 ; Proto-Oncogene Proteins - metabolism ; stem cells ; Substantia Nigra - pathology
  • É parte de: The EMBO journal, 2016-09, Vol.35 (18), p.1963-1978
  • Notas: Swedish Foundation for Strategic Research
    European Commission - No. FP7-HEALTH 602278; No. FP7-HEALTH 278871
    FEBS - No. Long-Term Fellowship 2007 to JCV
    istex:C8BD7AF1D1CC23D37B597EF99CE49E63C79D045F
    AppendixExpanded View Figures PDFReview Process File
    Cambridge Brain Bank
    Karolinska Institutet
    ark:/67375/WNG-C8969JGP-R
    Czech Ministry of Education and European Regional Development Fund - No. CZ.1.07/2.3.00/20.0180
    ArticleID:EMBJ201593725
    Swedish Research Council - No. VR 2008:2811; No. VR 2011:3116; No. VR 2011:3318
    NIH - No. 2RO1 HD043997; No. RO1 DE024745
    ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: 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. Synopsis PBX1 controls a novel transcriptional network required for midbrain dopaminergic specification and survival. PBX1 and its target NFE2L1 protect dopaminergic neurons from oxidative stress, and their levels are severely reduced in the substantia nigra of Parkinson's disease patients. Pbx1 is expressed in a subpopulation of dopaminergic neuroblasts and controls the specification and survival of midbrain dopaminergic neurons. 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. PBX1 and NFE2L1 protect dopaminergic neurons from oxidative stress. Nuclear PBX1 and NFE2L1 levels are severely reduced in midbrain dopaminergic neurons of Parkinson's disease patients. The homeobox factor PBX1 directly represses or activates key genes involved in specification, survival, and oxidative stress protection of midbrain dopaminergic neurons.
  • Editor: England: Blackwell Publishing Ltd
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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