Ccdc85c-Par3 凝聚物将细胞极性与 Notch 联系起来，以控制神经祖细胞的增殖。

Ccdc85c-Par3 condensates couple cell polarity with Notch to control neural progenitor proliferation.

机构信息

Department of Anesthesia, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; The Shanghai Key Laboratory of Medical Epigenetics, National Center for Neurological Disorders, Fudan University, Shanghai 200032, China.

出版信息

Cell Rep. 2023 Jul 25;42(7):112677. doi: 10.1016/j.celrep.2023.112677. Epub 2023 Jun 22.

DOI:10.1016/j.celrep.2023.112677

PMID:37352102

Abstract

Polarity proteins regulate the proliferation and differentiation of neural progenitors to generate neurons during brain development through multiple signaling pathways. However, how cell polarity couples the signaling pathways remains unclear. Here, we show that coiled-coil domain-containing protein 85c (Ccdc85c) interacts with the polarity protein Par3 to regulate the proliferation of radial glial cells (RGCs) via phase separation coupled to percolation (PSCP). We find that the interaction with Ccdc85c relieves the intramolecular auto-inhibition of Par3, which leads to PSCP of Par3. Downregulation of Ccdc85c causes RGC differentiation. Importantly, the open conformation of Par3 facilitates the recruitment of the Notch regulator Numb to the Par3 condensates, which might prevent the attenuation of Notch activity to maintain RGC proliferation. Furthermore, ectopic activation of Notch signaling rescues RGC proliferation defects caused by the downregulation of Ccdc85c. These results suggest that Ccdc85c-mediated PSCP of Par3 regulates Notch signaling to control RGC proliferation during brain development.

摘要

极性蛋白通过多种信号通路调节神经祖细胞的增殖和分化，以在大脑发育过程中产生神经元。然而，细胞极性如何与信号通路偶联尚不清楚。在这里，我们表明卷曲螺旋结构域蛋白 85c（Ccdc85c）与极性蛋白 Par3 相互作用，通过与渗透相关的相分离（PSCP）来调节放射状胶质细胞（RGC）的增殖。我们发现与 Ccdc85c 的相互作用解除了 Par3 的分子内自动抑制，从而导致 Par3 的 PSCP。Ccdc85c 的下调导致 RGC 分化。重要的是，Par3 的开放构象有利于 Notch 调节因子 Numb 募集到 Par3 凝聚物中，这可能防止 Notch 活性减弱以维持 RGC 增殖。此外，Notch 信号的异位激活挽救了 Ccdc85c 下调引起的 RGC 增殖缺陷。这些结果表明，Ccdc85c 介导的 Par3 的 PSCP 调节 Notch 信号，以在大脑发育过程中控制 RGC 的增殖。