蛋白运输调控因子Mgb抑制干细胞衍生脑肿瘤的机制研究

Correct establishment and maintenance of unidirectional Notch signaling is critical for the homeostasis of various stem cell lineages. Misregulation of Notch-mediated cell fate determination in stem cell lineages lead to various human diseases, including tissue dystrophy and cancer. Yet whether and how intracellular trafficking and processing of Notch receptor ensures asymmetric Notch activation and prevents ectopic Notch hyperactivation within stem cell lineages remains to be elucidated. In this project, we plan to use Drosophila type II neural stem cell lineages as an in vivo model system to reveal the molecular mechanisms by which the protein trafficking regulator Mega brain (Mgb) inhibits stem cell-derived brain tumor formation through ensuring asymmetric Notch activation in neural stem cells. We aim to understand 1) how Notch signaling is ectopically turned on in neural progenitors upon loss of Mgb, resulting in tumorigenesis; 2) how Mgb mediates Notch receptor intracellular trafficking; and 3) how the posttranslational modification of Notch receptor affects its endosomal sorting and processing in neural in neural stem cell lineages. Successful completion of this project promises to provide new mechanistic insights into the process of Notch-mediated stem cell fate decisions and ultimately help understand and treat stem cell-derived cancer and tissue dystrophy.

正确建立和维持单方向的Notch信号对多种干细胞系的稳态维持均至关重要。Notch信号介导的干细胞命运决定过程出现错误会引起包括组织器官萎缩和干细胞衍生癌症等在内的多种疾病的发生。然而，Notch受体的胞内运输和剪切加工何以确保Notch通路在干细胞-祖细胞间的不对称活化还尚不清楚。本项目将以果蝇幼虫中脑区II型神经干细胞作为模式，结合多种研究手段，探究蛋白运输调控因子Mgb通过调控Notch在神经干细胞-祖细胞间的不对称活化进而防止干细胞衍生脑肿瘤发生的分子机制。我们将阐明Notch信号在Mgb缺失时如何在神经祖细胞中被异位激活，并揭示Mgb如何调控Notch受体在神经干细胞系中的囊泡转运。这项研究的完成将有助于加深我们对干细胞谱系内Notch信号介导的细胞命运锁定过程的认识，为干细胞衍生癌症及器官萎缩等疾病的防治提供重要的理论依据。

单向 Notch 信号的正确建立和维持对于多种干细胞谱系的稳态维持都至关重要。然而，规避细胞自主性 Notch 信号异位激活及由此引发的细胞命运错误决定的分子机制仍不明晰。在这项工作中，我们发现Retromer复合体直接且特异性地调节果蝇神经干细胞谱系中的其货物蛋白 Notch 受体的逆行囊泡运输，从而确保从神经祖细胞到神经干细胞的单向 Notch 信号传导。由 E3 泛素连接酶 Itch/Su(dx) 介导的 Notch 多泛素化在神经祖细胞中效率较低，因而依赖 Retromer 复合体介导的高效蛋白转运来避免 Notch 受体的异常内体积累和细胞自主性信号激活。当 Retromer 复合体功能出现障碍时，低泛素化的 Notch 会在 Rab7+ 内体中过度积聚，并以配体依赖性方式被异位剪切加工和激活，进而导致神经祖细胞起源的脑肿瘤发生。因此，我们的研究结果揭示了一种新颖的保护机制，即 Retromer 复合体及时检测潜在有害的 Notch 受体，防止 Notch 异常激活所诱导的神经祖细胞去分化和脑肿瘤发生。