CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing

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.

Authors

Institutions

Publication Details

Journal
EMBO Molecular Medicine
Published
2025-09-08
DOI
https://doi.org/10.1038/s44321-025-00302-7
Citations
2
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
2.30
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing

Veronica Krenn, Xianrong Wong, Xianshu Bai, Frank Kirchhoff et al.
2 citations
EMBO Molecular Medicine
Microtubule and mitosis dynamics
2.30
article

CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing

Veronica Krenn, Xianrong Wong, Xianshu Bai, Frank Kirchhoff, Ruiying Yuan, Ruoxiao Xie, Hua Wang, Zhenming Guo, Na Jiang, Shan Bian, Qing‐Ran Bai, Xiao Mao, Wenhui Huang, Liu Deng, Yuan Wang, Zhen Liu, Yu Jin, Shiyi Liu, Huaizhe Zhan, Jing Xu
article en
2 citations

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.

EMBO Molecular MedicineVol. 17(10)
Tongji University (CN), Central South University (CN), Tibet University (CN), University of Liverpool (GB), Harbin Medical University (CN), Sun Yat-sen University (CN), China Pharmaceutical University (CN), National Health and Family Planning Commission (CN), Institute for Stem Cell Biology and Regenerative Medicine (IN), Sun Yat-sen Memorial Hospital (CN), Genetic Resources Center (JP), Tongji Hospital (CN), Hunan Provincial Maternal and Child Health Hospital (CN), University of Milano-Bicocca (IT), Brandeis University (US), Saarland University (DE), University of South China (CN)
Openalex Percentile: Top 11%
Microtubule and mitosis dynamics
2.30
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.