Knockout of Katnal2 Leads to Autism-like Behaviors and Developmental Delay in Zebrafish

Abstract

KATNAL2 mutations have been associated with autism spectrum disorder (ASD) and other related neurodevelopmental disorders (NDDs) such as intellectual disability (ID) in several cohorts. KATNAL2 has been implicated in brain development, as it is required for ciliogenesis in Xenopus and is required for dendritic arborization in mice. However, a causative relationship between the disruption of Katnal2 function and behavioral defects has not been established. Here, we generated a katnal2 null allele in zebrafish using CRISPR/Cas9-mediated genome editing and carried out morphological and behavioral characterizations. We observed that katnal2-/- embryos displayed delayed embryonic development especially during the convergence and extension (CE) movement. The hatched larvae showed reduced brain size and body length. In the behavioral tests, the katnal2-/- zebrafish exhibited reduced locomotor activity both in larvae and adults; increased nocturnal waking activity in larvae; and enhanced anxiety-like behavior, impaired social interaction, and reduced social cohesion in adults. These findings indicate an important role for katnal2 in development and behavior, providing an in vivo model to study the mechanisms underlying the ASD related to KATNAL2 mutations.