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A CRISPR activation screen reveals a cilia disassembly pathway mutated in focal cortical dysplasia

Shane D Elliott1, Paul J Ready1, Caitlin M Wrinn1

  • 1Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.

Science Advances
|October 29, 2025
PubMed

Insights

Scientists discovered a pathway controlling primary cilia disassembly, involving F2R, SARM1, and RhoA. Mutations in this pathway are linked to focal cortical dysplasia (FCD), a neurological disorder.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Genetics

Background:

  • Ciliopathies arise from defects in primary cilia assembly, but the mechanisms and disease relevance of cilia disassembly are unclear.
  • Primary cilia play crucial roles in cellular signaling and development, and their dysfunction is implicated in various diseases.

Purpose of the Study:

  • To identify negative regulators of ciliary function and uncover the pathway governing cilia disassembly.
  • To investigate the role of cilia disassembly in neurological disorders, specifically focal cortical dysplasia (FCD).

Main Methods:

  • Genome-wide CRISPR activation (CRISPRa) screening to identify genes regulating ciliary function.
  • Functional assays to characterize the identified pathway components (F2R, SARM1, ryanodine receptors, calcium signaling, RhoA) in cilia disassembly.
  • Analysis of patient-derived mutations in FCD and their impact on cilia and cortical development.

Main Results:

  • A functional pathway comprising F2R, sterile alpha and TIR motif-containing 1 (SARM1) hydrolase, ryanodine receptors, peri-centrosomal calcium signaling, and RhoA was identified as necessary and sufficient for cilia disassembly.
  • Somatic mutations in several pathway components are found in focal cortical dysplasia (FCD).
  • Patient-derived mutations in SARM1 and RhoA enhance cilia loss and impair cortical development, while SARM1 inhibition rescues cilia in FCD cells.

Conclusions:

  • A novel pathway regulating primary cilia disassembly has been elucidated.
  • Aberrant activation of this pathway, driven by FCD-associated mutations, contributes to neurological dysfunction.
  • CRISPRa screening is a powerful tool for uncovering disease mechanisms, particularly those involving somatic mutations.

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