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Ttyh1 regulates embryonic neural stem cell properties by enhancing the Notch signaling pathway
Author(s) -
Kim Juwan,
Han Dasol,
Byun SungHyun,
Kwon Mookwang,
Cho Jae Youl,
Pleasure Samuel J,
Yoon Keejung
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745472
Subject(s) - library science , engineering , microbiology and biotechnology , engineering ethics , political science , biology , computer science
Despite growing evidence linking Drosophila melanogaster tweety‐homologue 1 (Ttyh1) to normal mammalian brain development and cell proliferation, its exact role has not yet been determined. Here, we show that Ttyh1 is required for the maintenance of neural stem cell ( NSC ) properties as assessed by neurosphere formation and in vivo analyses of cell localization after in utero electroporation. We find that enhanced Ttyh1‐dependent stemness of NSC s is caused by enhanced γ‐secretase activity resulting in increased levels of Notch intracellular domain ( NICD ) production and activation of Notch targets. This is a unique function of Ttyh1 among all other Ttyh family members. Molecular analyses revealed that Ttyh1 binds to the regulator of γ‐secretase activity Rer1 in the endoplasmic reticulum and thereby destabilizes Rer1 protein levels. This is the key step for Ttyh1‐dependent enhancement of γ‐secretase activity, as Rer1 overexpression completely abolishes the effects of Ttyh1 on NSC maintenance. Taken together, these findings indicate that Ttyh1 plays an important role during mammalian brain development by positively regulating the Notch signaling pathway through the downregulation of Rer1.