Zebrafish knockout models of atxn1a, atxn1b, and atxn1l reveal distinct and shared phenotypic and transcriptomic...

Spinocerebellar ataxia type 1 is a progressive neurodegenerative disorder caused by polyglutamine expansion in ATXN1, yet the normal physiological roles of ATXN1 and its paralog ATXN1L remain incompletely understood. To define these roles, we generated the first zebrafish knockouts (KOs) of the three ataxin-1 family genes, atxn1a, atxn1b, and atxn1l, using CRISPR/Cas9 and performed phenotypic and transcriptomic analyses. All KOs exhibited reduced early survival and mild larval growth deficits. Behavioral assays revealed both shared and paralog-specific effects: atxn1a mutants displayed a reproducible light-dependent locomotor deficit, whereas atxn1b and atxn1l mutants showed generalized hypoactivity. Adult behavioral assessment revealed a gradient of phenotypic severity, with atxn1a KOs displaying the earliest and most pronounced alterations in vertical tank exploration and the greatest impairment in swim-tunnel performance. RNA-seq at 5 days post-fertilization identified extensive transcriptional alterations, including both shared and gene-specific differentially expressed genes associated with neural differentiation, microglial/immune cell migration, and immune signaling. Co-expression network analysis further identified distinct KO-associated gene modules, including a phototransduction-enriched module strongly correlated with atxn1a KO status, providing a potential mechanistic link to its light-dependent locomotor phenotype. Together, these findings define conserved and specialized roles of ATXN1-family genes in locomotor behavior, neurodevelopment, retinal function, and immune-related processes.