2025-10-29 イェール大学
<関連情報>
- https://news.yale.edu/2025/10/29/new-insight-how-cilia-cell-surfaces-break-down
- https://www.science.org/doi/10.1126/sciadv.aeb7238
CRISPR活性化スクリーニングにより、局所性皮質異 A CRISPR activation screen reveals a cilia disassembly pathway mutated in focal cortical dysplasia
Shane D. Elliott, Paul J. Ready, Caitlin M. Wrinn, Qianqian Ma, […] , and David K. Breslow
Science Advances Published:29 Oct 2025
DOI:https://doi.org/10.1126/sciadv.aeb7238
Abstract
Defective assembly of primary cilia causes ciliopathies, but cilia disassembly and its role in disease remain poorly understood. From a genome-wide CRISPR activation (CRISPRa) screen for negative regulators of ciliary function, we find here that the F2R G protein–coupled receptor, sterile alpha and TIR motif-containing 1 (SARM1) hydrolase, ryanodine receptors, peri-centrosomal calcium signaling, and RhoA form a functional pathway that is necessary and sufficient for cilia disassembly. Highlighting the significance of this pathway, several components are somatically mutated in focal cortical dysplasia (FCD), a neurological disorder characterized by intractable epilepsy. Supporting the functional impact of these variants, patient-derived SARM1 and RhoA mutations potentiate cilia loss, and a RhoA variant impairs cortical development. Conversely, SARM1 inhibition restores cilia in cells with FCD-associated alterations. Together, our work identifies a pathway for cilia disassembly, implicates aberrant pathway activation as a feature of FCD-associated mutations, and illustrates the potential of CRISPRa screening to provide insight into diseases caused by somatic mutations.
