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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 LU ; Kaiser, Karol; Islam, Saiful; Gyllborg, Daniel and Laguna-Goya, Rocio, et al. (2016) In EMBO Journal 35(18). p.78-1963
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... (More)

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.

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publication status
published
keywords
Journal Article
in
EMBO Journal
volume
35
issue
18
pages
16 pages
publisher
Oxford University Press
external identifiers
  • scopus:84979075767
ISSN
1460-2075
DOI
10.15252/embj.201593725
language
English
LU publication?
no
id
33f44869-60b1-43fa-b2d6-69f5a1dcc395
date added to LUP
2016-11-23 13:04:55
date last changed
2017-10-01 05:26:15
@article{33f44869-60b1-43fa-b2d6-69f5a1dcc395,
  abstract     = {<p>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.</p>},
  author       = {Villaescusa, J Carlos and Li, Bingsi and Toledo, Enrique M and Rivetti di Val Cervo, Pia and Yang, Shanzheng and Stott, Simon Rw and Kaiser, Karol and Islam, Saiful and Gyllborg, Daniel and Laguna-Goya, Rocio and Landreh, Michael and Lönnerberg, Peter and Falk, Anna and Bergman, Tomas and Barker, Roger A and Linnarsson, Sten and Selleri, Licia and Arenas, Ernest},
  issn         = {1460-2075},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {09},
  number       = {18},
  pages        = {78--1963},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {A PBX1 transcriptional network controls dopaminergic neuron development and is impaired in Parkinson's disease},
  url          = {http://dx.doi.org/10.15252/embj.201593725},
  volume       = {35},
  year         = {2016},
}