Transcriptome analysis of Katnal2 knock-out mutant and wild-type mice

Autism spectrum disorders (ASD) frequently accompany macrocephaly, which could involve hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-related protein strongly implicated in ASD. However, it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule-related cellular deficits and ASD-related phenotypes. We found here that Katnal2-KO mice display social communication deficits, including excessive courtship ultrasonic vocalizations and decreased mating success. Katnal2-KO brains show age-dependent ventricular enlargements and motile ciliary deficits in ependymal cells lining ventricular walls. Katnal2-KO hippocampal neurons, surrounded by lateral ventricles, show limited blood volumes and flow and age-dependent synaptic functional deficits involving synaptic gene downregulation and ASD-like transcriptomic changes. Early postnatal Katnal2 re-expression prevents the ventricular and behavioral phenotypes in Katnal2-KO adults. These results suggest that Katnal2 critically regulates ependymal ciliary function, ventricular volume, CSF circulation, synaptic function, and social communication and that ependymal ciliopathies could underlie ASD-related macrocephaly, ventriculomegaly, and hydrocephalus