CELF2 Promotes Tau Exon 10 Inclusion Via Hinge Domain-Mediated Nuclear Condensation

ABSTRACT: Alternative splicing is a fundamental process that contributes to the functional diversity and complexity of proteins. The regulation of each alternative splicing event involves the coordinated action of multiple RNA-binding proteins, creating a diverse array of alternatively spliced products. Dysregulation of alternative splicing is associated with various diseases, including neurodegeneration. Here we demonstrate that CELF2 binds mRNAs associated with neurodegenerative diseases, with a specific interaction observed in the intron adjacent to exon 10 on tau mRNA. Loss of CELF2 in the mouse brain results in a decreased inclusion of tau exon 10, leading to a reduced 4R:3R ratio. The hinge domain of CELF2 possesses an intrinsically disordered region (IDR), which mediates CELF2 condensation. The IDR is required for CELF2 activity in promoting tau exon 10 inclusion and can be functionally replaced by the IDRs of FUS or TAF15. With CRISPR-based imaging, we showed that CELF2 condensates colocalize with tau RNA. Using TurboID, we identified proteins that interact with CELF2 through its IDR. CELF2 co-condensates with NOVA2 and SFPQ, which coordinate with CELF2 to regulate the alternative splicing of Tau exon 10. We found that a conserved negatively charged residue within the IDR (D388) was critical for CELF2 condensate formation, its interactions with NOVA2 and SFPQ, and its function in regulating tau exon 10 splicing. Finally, we revealed that CELF2 condensation capacity is associated with 4R tau expression in vivo, impacting locomotor and cognitive function. Our data suggest that CELF2 regulates tau alternative splicing by forming condensates through its IDR with other splicing factors, and that the composition of the proteins within the condensates determines the balance of tau isoforms to impact neuronal function.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Zhao Zhang  

LAB HEAD: Lizhen Chen

PROVIDER: PXD070265 | Pride | 2026-07-28

REPOSITORIES: Pride