通过神经上皮祖细胞中的 NUMB 运输进行 EGFR 信号终止控制出生后神经发生龛的分化。

EGFR Signaling Termination via Numb Trafficking in Ependymal Progenitors Controls Postnatal Neurogenic Niche Differentiation.

机构信息

Department of Cell Biology, Duke University, School of Medicine, Durham, NC 27710, USA.

Department of Cell Biology, Duke University, School of Medicine, Durham, NC 27710, USA; Department of Neurobiology, Duke University, School of Medicine, Durham, NC 27710, USA; Preston Robert Tisch Brain Tumor Center, Duke University, School of Medicine, Durham, NC 27710, USA; Institute for Brain Sciences, Duke University, School of Medicine, Durham, NC 27710, USA.

出版信息

Cell Rep. 2019 Aug 20;28(8):2012-2022.e4. doi: 10.1016/j.celrep.2019.07.056.

DOI:10.1016/j.celrep.2019.07.056

PMID:31433979

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6768562/

Abstract

Specialized microenvironments, called niches, control adult stem cell proliferation and differentiation. The brain lateral ventricular (LV) neurogenic niche is generated from distinct postnatal radial glial progenitors (pRGPs), giving rise to adult neural stem cells (NSCs) and niche ependymal cells (ECs). Cellular-intrinsic programs govern stem versus supporting cell maturation during adult niche assembly, but how they are differentially initiated within a similar microenvironment remains unknown. Using chemical approaches, we discovered that EGFR signaling powerfully inhibits EC differentiation by suppressing multiciliogenesis. We found that EC pRGPs actively terminated EGF activation through receptor redistribution away from CSF-contacting apical domains and that randomized EGFR membrane targeting blocked EC differentiation. Mechanistically, we uncovered spatiotemporal interactions between EGFR and endocytic adaptor protein Numb. Ca-dependent basolateral targeting of Numb is necessary and sufficient for proper EGFR redistribution. These results reveal a previously unknown cellular mechanism for neighboring progenitors to differentially engage environmental signals, initiating adult stem cell niche assembly.

摘要

特定的微环境，称为龛，控制成人干细胞的增殖和分化。脑侧脑室（LV）神经发生龛源于不同的出生后放射状胶质祖细胞（pRGPs），产生成体神经干细胞（NSCs）和龛室室管膜细胞（ECs）。细胞内在程序在成年龛室组装过程中控制干细胞与支持细胞的成熟，但它们在相似的微环境中如何被差异启动仍不清楚。我们使用化学方法发现，EGFR 信号通过抑制多纤毛发生强烈抑制 EC 分化。我们发现，EC pRGPs 通过将受体从与 CSF 接触的顶端区域重新分配来主动终止 EGF 的激活，并且随机的 EGFR 膜靶向阻止了 EC 分化。从机制上讲，我们揭示了 EGFR 和内吞衔接蛋白 NUMB 之间的时空相互作用。NUMB 的 Ca 依赖性基底外侧靶向对于正确的 EGFR 再分配是必需和充分的。这些结果揭示了一种先前未知的细胞机制，用于相邻祖细胞差异地参与环境信号，启动成年干细胞龛室组装。