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Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures

ABSTRACT: De novo heterozygous variants in CELF2 have recently been associated with a rare neurodevelopmental disorder, yet the mechanisms linking specific variants to distinct clinical phenotypes remain poorly understood. Here, we report a cohort of 18 individuals and provide evidence that variants causing CELF2 mislocalization, but not protein-null variants, are associated with seizures. Using proband-derived induced pluripotent stem cells and transgenic mouse models, we demonstrate that CELF2 undergoes activity-dependent nucleocytoplasmic shuttling in excitatory neurons and that its cytoplasmic retention causes neuronal hyperactivity, elevated seizure susceptibility, and learning and memory deficits. Cytoplasmic CELF2 regulates mRNAs critical for synaptic function and neuronal excitability and is implicated in epileptic seizures and intellectual disability. Drug screening further identifies AKT signaling as a key regulator of CELF2 nucleocytoplasmic shuttling and a candidate target for reversing neuronal hyperactivity. Together, our findings expand the clinical and genetic spectrum of CELF2-related neurodevelopmental disorders and establish a variant-specific mechanism that links CELF2 mislocalization to neuronal hyperactivity, seizures, and cognitive impairment.

ORGANISM(S): Mus musculus

PROVIDER: GSE325228 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci discovered early in maturation of three-dimensional cortical organoids from DM1 patient-derived induced pluripotent stem cells, cause hyperphosphorylation of CUGBP Elav-Like Family Member 2 (CELF2 ) protein. Integrative single-cell RNA-seq and enhanced crosslinking and immunoprecipitation (eCLIP ) analysis revealed reduced CELF2 protein-RNA substrate interactions resulting in mis-regulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the Methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(-/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-Methyl-D-aspartic acid (NMDA ) antagonists as potential treatment avenues for neuronal defects in DM1. To evaluate if the post-translational modification of CELF2 impacts its RNA targets, we generated transcriptome-wide eCLIP maps of CELF2 protein-RNA interactions in mature, 6-month-old control and DM1 cortical organoids. All CELF2 eCLIP libraries per organoid line were performed in biologically independent duplicates, with each replicate experiment consisting of a CELF2 (IP) and a paired size-matched input (SMInput) library . We used CLIPper to identify clusters of reads representing regions in the transcriptome significantly associated with CELF2 binding in both neurotypical lines and compared them to DM1 cortical organoids with 600 and 1200 CUG repeats.

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Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures

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