N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development

作者全名："Ma, Zhihua; Zeng, Yi; Wang, Ming; Liu, Wei; Zhou, Jiafeng; Wu, Chao; Hou, Lin; Yin, Bin; Qiang, Boqin; Shu, Pengcheng; Peng, Xiaozhong"

作者地址："[Ma, Zhihua; Zeng, Yi; Wang, Ming; Liu, Wei; Zhou, Jiafeng; Wu, Chao; Hou, Lin; Yin, Bin; Qiang, Boqin; Shu, Pengcheng; Peng, Xiaozhong] Inst Basic Med Sci, Chinese Acad Med Sci, Med Primate Res Ctr, Sch Basic Med,Peking Union Med Coll,Dept Mol Biol, Beijing, Peoples R China; [Hou, Lin; Yin, Bin; Qiang, Boqin; Shu, Pengcheng] State Key Lab Common Mech Res Major Dis, Beijing, Peoples R China; [Shu, Pengcheng] Chinese Inst Brain Res, Beijing, Peoples R China; [Peng, Xiaozhong] State Key Lab Resp Hlth & Multimorbid, Beijing, Peoples R China; [Peng, Xiaozhong] Chinese Acad Med Sci, Inst Lab Anim Sci, Peking Union Med Coll, Beijing, Peoples R China; [Zeng, Yi] Chongqing Med Univ, Inst Viral Hepatitis, Dept Infect Dis, Key Lab Mol Biol Infect Dis,Minist Educ,Affiliated, Chongqing, Peoples R China; [Wang, Ming] Capital Med Univ, Beijing Tongren Hosp, Beijing Inst Otolaryngol, Dept Otolaryngol Head & Neck Surg,Beijing Key Lab, Beijing, Peoples R China"

通信作者："Shu, PC; Peng, XZ (通讯作者)，Inst Basic Med Sci, Chinese Acad Med Sci, Med Primate Res Ctr, Sch Basic Med,Peking Union Med Coll,Dept Mol Biol, Beijing, Peoples R China.; Shu, PC (通讯作者)，State Key Lab Common Mech Res Major Dis, Beijing, Peoples R China.; Shu, PC (通讯作者)，Chinese Inst Brain Res, Beijing, Peoples R China.; Peng, XZ (通讯作者)，State Key Lab Resp Hlth & Multimorbid, Beijing, Peoples R China.; Peng, XZ (通讯作者)，Chinese Acad Med Sci, Inst Lab Anim Sci, Peking Union Med Coll, Beijing, Peoples R China."

来源：EMBO JOURNAL

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001081059900001

JCR分区：Q1

影响因子：9.4

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：N4BP1; neocortical development; Notch signaling; RAM domain; Trim21

摘要："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."

基金机构："We thank Professor Weimin Zhong (Yale University) for providing constructive suggestions for the project, Professor Mengsheng Qiu (Hangzhou Normal University) for the ISH technology guidance, and Professor Yan Zhou (Wuhan University) for the gift of differ [31970772, 32370883, 2021ZD0200902]; National Natural Science Foundation of China [2021-1-I2M-019, 2021-1-I2M-024]; CAMS Innovation Fund for Medical Sciences (CIFMS)"

基金资助正文："We thank Professor Weimin Zhong (Yale University) for providing constructive suggestions for the project, Professor Mengsheng Qiu (Hangzhou Normal University) for the ISH technology guidance, and Professor Yan Zhou (Wuhan University) for the gift of different plasmids and N1E-115 cell lines. This work was supported by grants from the National Natural Science Foundation of China (31970772 and 32370883 to P.S.), National Science and Technology Innovation 2030 Grants (2021ZD0200902 to X.P.), and the CAMS Innovation Fund for Medical Sciences (CIFMS; 2021-1-I2M-019 to P.S. and 2021-1-I2M-024 to X.P.)."