Xiangbin Jia1 · Wenqi Xie1 · Bing Du1 · Mei He1,6 · Jia Chen1,7 · Meilin Chen1 · Ge Zhang1 · Ke Wang2 · Wanjing Xu3 · Yuxin Liao1 · Senwei Tan1 · Yongqing Lyu1 · Bin Yu1 · Zihang Zheng1 · Xiaoyue Sun1 · Yang Liao1 · Zhengmao Hu1,4 · Ling Yuan1,4 · Jieqiong Tan1,4 · Kun Xia1,3 · Hui Guo1,5
1 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, MOE Key Laboratory of Rare Pediatric Disease, School of Life Sciences, Central South University, Changsha 410078, China
2 School of Medicine, Kunming University of Science and Technology, Kunming 650500, China
3 Hengyang Medical School, University of South China, Hengyang 421001, China
4 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha 410078, China
5 Furong Laboratory, Changsha 410078, China
6 NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410000, China
7 Key Laboratory of Neurodegenerative Disorders in Hunan Province, Central South University, Changsha 410008, China
Abstract
Loss-of-function variants in CSDE1 have been strongly linked to neuropsychiatric disorders, yet the precise role of CSDE1 in neurogenesis remains elusive. In this study, we demonstrate that knockout of Csde1 during cortical development in mice results in impaired neural progenitor proliferation, leading to abnormal cortical lamination and embryonic lethality. Transcriptomic analysis revealed that Csde1 upregulates the transcription of genes involved in the cell cycle network. Applying a dual thymidine-labelling approach, we further revealed prolonged cell cycle durations of neuronal progenitors in Csde1-knockout mice, with a notable extension of the G1 phase. Intersection with CLIP-seq data demonstrated that Csde1 binds to the 3′ untranslated region (UTR) of mRNA transcripts encoding cell cycle genes. Particularly, we uncovered that Csde1 directly binds to the 3′ UTR of mRNA transcripts encoding Cdk6, a pivotal gene in regulating the transition from the G1 to S phases of the cell cycle, thereby maintaining its stability. Collectively, this study elucidates Csde1 as a novel regulator of Cdk6, sheds new light on its critical roles in orchestrating brain development, and underscores how mutations in Csde1 may contribute to the pathogenesis of neuropsychiatric disorders.
Keywords
Csde1; Neurogenesis; Autism spectrum disorder; Cell cycle; Cdk6
