Modeling Neurodevelopmental Disorders and Epilepsy Caused by Loss of Function of kif2a in Zebrafish.

In recent years there has been extensive research on malformations of cortical development (MCDs) that result in clinical features like developmental delay, intellectual disability, and drug-resistant epilepsy (DRE). Various studies highlighted the contribution of microtubule-associated genes (including tubulin and kinesin encoding genes) in MCD development. It has been reported that de novo mutations in KIF2A, a member of the kinesin-13 family, are linked to brain malformations and DRE. Although it is known that KIF2A functions by regulating microtubule depolymerization via an ATP-driven process, in vivo implications of KIF2A loss of function remain partly unclear. Here, we present a novel kif2a knockout zebrafish model, showing hypoactivity, habituation deficits, PTZ-induced seizure susceptibility and microcephaly as well as neuronal cell proliferation defects and increased apoptosis. Interestingly, kif2a-/- larvae survived until adulthood and were fertile. Notably, our kif2a zebrafish knockout model demonstrated many phenotypic similarities to KIF2A mouse models. This study provides valuable insights into the functional importance of kif2a in zebrafish and phenotypical hallmarks related to KIF2A mutations. Ultimately, this model could be used in a future search for more effective therapies that alleviate the clinical symptoms typically associated with MCDs. Significance statement This study addresses the functional importance of Kif2a and the phenotypical hallmarks related to KIF2A mutations in zebrafish. We generated a novel kif2a loss of function model in zebrafish and demonstrated that Kif2a deficiency was associated with behavioural alterations, habituation deficits, enhanced susceptibility to seizures, microcephaly, neuronal cell proliferation defects and increased apoptosis. These findings provide insights into a better understanding of the kif2a-related pathological mechanisms and, eventually, might help in the search for novel and more effective medications to alleviate clinical symptoms typically associated with MCDs.