N4BP1 mediates RAM domain‐dependent notch signaling turnover during neocortical development
N4BP1 mediates RAM domain‐dependent notch signaling turnover during neocortical development
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DOI：
10.15252/embj.2022113383
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发表时间：
2023-10
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通讯作者：
Zhihua Ma;Yi Zeng;Ming Wang;Wei Liu;Jiafeng Zhou;Chao Wu;Lin Hou;Bin Yin;Boqin Qiang;P. Shu;Xiaozhong Peng
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作者：
Zhihua Ma;Yi Zeng;Ming Wang;Wei Liu;Jiafeng Zhou;Chao Wu;Lin Hou;Bin Yin;Boqin Qiang;P. Shu;Xiaozhong Peng
Notch信号通路活性，特别是生物活性效应片段NICD的波动，是干细胞中正确命运决定的快速有效动态调节所必需的。在这项研究中，我们确定了NEDD 4结合蛋白1（N4 BP 1），它在发育中的小鼠大脑皮层中高度表达，作为神经祖细胞中Notch信号动力学的负调节剂。有趣的是，N4 BP 1通过泛素介导的降解在Notch 1 S3切割后特异性地调节NICD稳定性，该降解依赖于其RAM结构域，而不是其PEST结构域，如之前广泛描述的那样。N4 BP 1中的CoCUN结构域，特别是“Phe-Pro”基序（862/863氨基酸），对于介导NICD降解是必不可少的。与其他NEDD 4家族成员相比，环家族E3连接酶Trim 21是N4 BP 1调控的NICD降解所必需的。N4 BP 1在皮质神经祖细胞中的过表达促进神经干细胞分化，而缺乏N4 BP 1的神经祖细胞对Notch信号转导敏感，导致神经祖细胞中干细胞样特性的维持和皮质神经元的产生降低。
Notch signaling pathway activity, particularly fluctuations in the biologically active effector fragment NICD, is required for rapid and efficient dynamic regulation of proper fate decisions in stem cells. In this study, we identified NEDD4‐binding protein 1 (N4BP1), which is highly expressed in the developing mouse cerebral cortex, as a negative modulator of Notch signaling dynamics in neural progenitor cells. Intriguingly, N4BP1 regulated NICD stability specifically after Notch1 S3 cleavage through ubiquitin‐mediated degradation that depended on its RAM domain, not its PEST domain, as had been extensively and previously described. The CoCUN domain in N4BP1, particularly the “Phe‐Pro” motif (862/863 amino acid), was indispensable for mediating NICD degradation. The Ring family E3 ligase Trim21 was, in contrast to other NEDD4 family members, required for N4BP1‐regulated NICD degradation. Overexpression of N4BP1 in cortical neural progenitors promoted neural stem cell differentiation, whereas neural progenitor cells lacking N4BP1 were sensitized to Notch signaling, resulting in the maintenance of stem‐like properties in neural progenitor cells and lower production of cortical neurons.