Deficiency of DDX3X results in neurogenesis defects and abnormal behaviors via dysfunction of the Notch signaling

• 成果类型: Article
• 署名作者: Duan, Weicheng; Huang, Guiyang; Sui, Yang; Wang, Kang; Yu, Yuxin; Chu, Xufeng; Cao, Xu; Chen, Liangpei; Liu, Jiahui; Eichler, Evan E.; Xiong, Bo
• 署名单位: Huazhong University of Science & Technology; Huazhong University of Science & Technology; University of Washington; University of Washington Seattle; Nanjing Medical University; Huazhong University of Science & Technology; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; Huazhong University of Science & Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11323
• DOI: 10.1073/pnas.2404173121
• 发表日期: 2024-11-05
• 关键词: rubinstein-taybi syndrome; pancreatic-cancer cells; mutations; autism; ddx3x; MODEL; differentiation; RECRUITMENT; disability; neurons

摘要

The molecular mechanisms underlying the neurodevelopmental disorders (NDDs) caused by DDX3X variants remain poorly understood. In this study, we validated that de novo DDX3X variants are enriched in female developmental delay (DD) patients and mainly affect the evolutionarily conserved amino acids based on a meta- analysis of 46,612 NDD trios. We generated a ddx3x deficient zebrafish allele, which exhibited reduced survival rate, DD, microcephaly, adaptation defects, anxiolytic behaviors, social interaction deficits, and impaired spatial recognitive memory. As revealed by single- nucleus RNA sequencing and biological validations, ddx3x deficiency leads to reduced neural stem cell pool, decreased total neuron number, and imbalanced differentiation of excitatory and inhibitory neurons, which are responsible for the behavioral defects. Indeed, the supplementation of L- glutamate or glutamate receptor agonist ly404039 could partly rescue the adaptation and social deficits. Mechanistically, we reveal that the ddx3x deficiency attenuates the stability of the crebbp mRNA, which in turn causes downregulation of Notch signaling and defects in neurogenesis. Our study sheds light on the molecular pathology underlying the abnormal neurodevelopment and behavior of NDD patients with DDX3X mutations, as well as providing potential therapeutic targets for the precision treatment.