CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing
Year: 2025
Type: article
Abstract: Primary microcephaly, a rare congenital condition characterized by reduced brain size, occurs due to impaired neurogenesis during brain development. Through whole-exome sequencing, we identified compound heterozygous loss-of-function mutations in CENTRIN 3 (CETN3) in a 5-year-old patient with primary microcephaly. As CETN3 has not been previously linked to microcephaly, we investigated its potential function in neurodevelopment in human pluripotent stem cell-derived cerebral organoids. We showed that CETN3-knockout (KO) organoids successfully recapitulated the microcephaly phenotype of reduced size compared to the control organoids. Through transcriptomic, histological, and protein analyses, we found that CETN3 deficiency directly interferes with neuronal differentiation and reduces proliferative capacity in neural stem/progenitor cells by impairing centrosome assembly required in cell cycle progression, consequently activating apoptosis. Furthermore, our data uncovered previously undocumented indirect effects of CETN3 through interaction with RNA splicing machinery involved in brain development. These findings expand the scope of known regulatory mechanisms of CETN3 in brain development and its etiological roles in human brain malformation.
Source: EMBO Molecular Medicine
Authors: Jing Xu, Xiao Mao, Zhen Liu, Na Jiang, Xin E Wong, Deng Liu, Yuan Wang, Huaizhe Zhan, Shiyi Liu, Jiayao Yu, Ruiying Yuan, Qingran Bai, Xianshu Bai, Wenhui Huang, Ruoxiao Xie, Veronica Krenn, Frank Kirchhoff, Hua Wang, Zhenming Guo, Shan Bian
Institutions: Tongji University, Shanghai East Hospital, Hunan Provincial Maternal and Child Health Hospital, University of South China, Harbin Medical University, Brandeis University, Tibet University, China Pharmaceutical University, Saarland University, Sun Yat-sen University, Sun Yat-sen Memorial Hospital, University of Liverpool, University of Milano-Bicocca, Central South University
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
OpenAlex ID: W4414085235