2025/09/08 by Jing Xu, Xiao Mao, Zhen Liu +17 · 1 voice
Biochemistry, Genetics and Molecular Biology · #Microtubule and mitosis dynamics #Pluripotent Stem Cells Research #Epigenetics and DNA Methylation
paper · doi:10.1038/s44321-025-00302-7
openalex publication_date 2025/09/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
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.