Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis

doi:10.1038/s41419-023-06071-w

	Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis
	Yao, Fenyong1 ; Huang, Shisheng1,2,3 ; Liu, Jiahui 1; Tan, Chunhua1 ; Xu, Mengqi1 ; Wang, Dengkui1 ; Huang, Maoqing1 ; Zhu, Yiyao4 ; Huang, Xingxu1 ; He, Shuijin1,5
	2023
发表期刊	CELL DEATH AND DISEASE (IF:8.1[JCR-2023],8.6[5-Year])
ISSN	2041-4889
卷号	14 期号:8
发表状态	已发表
DOI	10.1038/s41419-023-06071-w
摘要	Haploinsufficient mutation in arginine and glutamine-rich protein 1 (Arglu1), a newly identified pre-mRNA splicing regulator, may be linked to neural developmental disorders associated with mental retardation and epilepsy in human patients, but the underlying causes remain elusive. Here we show that ablation of Arglu1 promotes radial glial cell (RG) detachment from the ventricular zone (VZ), leading to ectopic localized RGs in the mouse embryonic cortex. Although they remain proliferative, ectopic progenitors, as well as progenitors in the VZ, exhibit prolonged mitosis, p53 upregulation and cell apoptosis, leading to reduced neuron production, neuronal loss and microcephaly. RNA seq analysis reveals widespread changes in alternative splicing in the mutant mouse embryonic cortex, preferentially affecting genes involved in neuronal functions. Mdm2 and Mdm4 are found to be alternatively spliced at the exon 3 and exon 5 respectively, leading to absence of the p53-binding domain and nonsense-mediated mRNA decay (NMD) and thus relieve inhibition of p53. Removal of p53 largely rescues the microcephaly caused by deletion of Arglu1. Our findings provide mechanistic insights into cortical malformations of human patients with Arglu1 haploinsufficient mutation.
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收录类别	SCI
语种	英语
资助项目	We thank Dr. Shaoyu Ge (Stony Brook University, SUNY, New York) for helpful discussion. We thank Dr. Ke Tang (Nanchang University, Nanchang, China) for kindly providing Emx1-Cre knock-in and COUP-TFI^fl/fl mice.[81870734] ; null[STI2030-Major Projects-2021ZD0202500]
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:001053844900003
出版者	SPRINGERNATURE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/319417
专题	生命科学与技术学院信息科学与技术学院生命科学与技术学院_PI研究组_何水金组生命科学与技术学院_PI研究组_黄行许组生命科学与技术学院_硕士生生命科学与技术学院_博士生生命科学与技术学院_本科生信息科学与技术学院_博士生
通讯作者	Huang, Xingxu; He, Shuijin
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 2.Chinese Acad Sci, Inst Neurosci, Shanghai Inst Biol Sci, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.ShanghaiTech Univ, Sch Informat Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 5.Shanghai Clin Res & Trial Ctr, Shanghai 201210, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Yao, Fenyong,Huang, Shisheng,Liu, Jiahui,et al. Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis[J]. CELL DEATH AND DISEASE,2023,14(8).
APA	Yao, Fenyong.,Huang, Shisheng.,Liu, Jiahui.,Tan, Chunhua.,Xu, Mengqi.,...&He, Shuijin.(2023).Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis.CELL DEATH AND DISEASE,14(8).
MLA	Yao, Fenyong,et al."Deletion of ARGLU1 causes global defects in alternative splicing in vivo and mouse cortical malformations primarily via apoptosis".CELL DEATH AND DISEASE 14.8(2023).