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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

Title
Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells
Author
정승준
Keywords
DOPAMINERGIC NEURON DEVELOPMENT; FLOOR PLATE; INT-1 PROTOONCOGENE; ANTERIOR HINDBRAIN; FGF; BRAIN; GENE; DIFFERENTIATION; IDENTITY; XENOPUS
Issue Date
2018-04
Publisher
NATURE PUBLISHING GROUP
Citation
EXPERIMENTAL AND MOLECULAR MEDICINE, v. 50, Article no. 24
Abstract
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.
URI
https://www.nature.com/articles/s12276-018-0044-yhttps://repository.hanyang.ac.kr/handle/20.500.11754/118273
ISSN
1226-3613; 2092-6413
DOI
10.1038/s12276-018-0044-y
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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