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Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells

 Ji Young Kim  ;  Jae Souk Lee  ;  Hyun Sub Hwang  ;  Dongjin R Lee  ;  Chul-Yong Park  ;  Sung Jun Jung  ;  Young Rang You  ;  Dae-Sung Kim  ;  Dong-Wook Kim 
 Experimental and Molecular Medicine, Vol.50(4) : 24, 2018 
Journal Title
 Experimental and Molecular Medicine 
Issue Date
The canonical Wnt signal pathway plays a pivotal role in anteroposterior patterning and midbrain specification during early neurogenesis. Activating Wnt signal has been a strategy for differentiating human pluripotent stem cells (PSCs) into midbrain dopaminergic (DA) neurons; however, the underlying molecular mechanism(s) of how the Wnt signal drives posterior fate remained unclear. In this study, we found that activating the canonical Wnt signal significantly upregulated the expression of EN1, a midbrain-specific marker, in a fibroblast growth factor signal-dependent manner in human PSC-derived neural precursor cells (NPCs). The EN1 promoter region contains a putative TCF4-binding site that directly interacts with the beta-catenin/TCF complex upon Wnt signal activation. Once differentiated, NPCs treated with a Wnt signal agonist gave rise to functional midbrain neurons including glutamatergic, GABAergic, and DA neurons. Our results provide a potential molecular mechanism that underlies midbrain specification of human PSC-derived NPCs by Wnt activation, as well as a differentiation paradigm for generating human midbrain neurons that may serve as a cellular platform for studying the ontogenesis of midbrain neurons and neurological diseases relevant to the midbrain.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Park, Chul Yong(박철용) ORCID logo https://orcid.org/0000-0002-4467-9268
Hwang, Hyun Sub(황현섭)
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