Informace o publikaci

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


VILLAESCUSA RAMIREZ Juan Carlos LI Bingsi TOLEDO Enrique RIVETTI DI VAL CERVO Pia YANG Shanzeng SIMON Stott KAISER Karol SAIFUL Islam DANIEL Gyllborg ROCIO Laguna-Goya MICHAEL Landreh PETER Lonnerbeg ANNA Falk TOMAS Bergman ROGER Barker STEN Linnarsson LICIA Selleri ERNEST Arenas

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj The EMBO Journal
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Obor Imunologie
Klíčová slova ChIP-Seq; dopamine; dopaminergic differentiation; stem cells; mesencephalon
Přiložené soubory
Popis 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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