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Updated: Jul 2, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Deletion of Fbxo25 causes excessive repetitive behavior, impaired recognition memory, reduced dendritic complexity,
Szu-Yu Lin1, Ho-Ching Chang1, Ya-Han Chang1
1Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract:
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and restricted repetitive behaviors. Genetic studies have implicated chromosomal microdeletions in the 8p23.2-pter region in ASD and related disorders, highlighting FBXO25 as a candidate gene. FBXO25 encodes an F-box protein component of the SCF E3 ubiquitin ligase complex, which is involved in protein degradation through the ubiquitin-proteasome system. To investigate the impact of FBXO25 deletion, we generated Fbxo25-deficient mice and conducted behavioral, structural, molecular, transcriptomic, and proteomic analyses. Homozygous Fbxo25 mutant mice exhibited excessive self-grooming, a core ASD-related repetitive behavior. In contrast, both heterozygous and homozygous mice displayed impaired recognition memory in the novel object recognition test. However, social behaviors, anxiety-like responses, and spatial memory were preserved. Golgi staining revealed reduced dendritic complexity in hippocampal dentate gyrus granule cells of both heterozygous and homozygous mice. Western blotting revealed altered protein expression, including decreased PSD95 and CaMKII alpha, and elevated Arc in homozygous mice. Transcriptomic and proteomic analyses identified 17 differentially expressed proteins (DEPs) shared between heterozygous and homozygous mutants, supporting a model of FBXO25 haploinsufficiency. Many DEPs are involved in focal adhesion, cytoskeletal organization, synaptic transmission and signaling, oxidative stress, and protein degradation. These findings suggest that FBXO25 deletion impairs ubiquitin-mediated degradation, leading to synaptic dysfunction and ASD-relevant phenotypes. Our study establishes a novel mouse model of FBXO25 deficiency. It provides mechanistic insight into how disrupted protein degradation may contribute to ASD pathogenesis, highlighting protein degradation as a potential therapeutic target.
