College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea.
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
EMBO Rep. 2018 Nov;19(11). doi: 10.15252/embr.201745472. Epub 2018 Sep 3.
Despite growing evidence linking 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 analyses of cell localization after electroporation. We find that enhanced Ttyh1-dependent stemness of NSCs 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.
尽管越来越多的证据表明 tweety-homologue 1（Ttyh1）与正常哺乳动物大脑发育和细胞增殖有关，但它的确切作用尚未确定。在这里，我们表明 Ttyh1 对于维持神经干细胞（NSC）特性是必需的，这可以通过神经球形成和电穿孔后细胞定位分析来评估。我们发现，增强的 Ttyh1 依赖性 NSC 干性是由增强的γ-分泌酶活性引起的，导致 Notch 细胞内结构域（NICD）产生增加和 Notch 靶基因的激活。这是 Ttyh1 在所有其他 Ttyh 家族成员中的独特功能。分子分析表明，Ttyh1 在内质网中与γ-分泌酶活性调节剂 Rer1 结合，从而破坏 Rer1 蛋白水平。这是 Ttyh1 依赖性增强γ-分泌酶活性的关键步骤，因为 Rer1 的过表达完全消除了 Ttyh1 对 NSC 维持的影响。总之，这些发现表明 Ttyh1 通过下调 Rer1 正向调节 Notch 信号通路，在哺乳动物大脑发育过程中发挥重要作用。
