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bioRxiv · 10.1101/2023.07.03.547302

ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus

Qiu, S.·Cao, H.·Xue, Y.·Zhao, W.·Xie, S.·Wu, N.·Song, M.·Pan, Y.-H.·Baas, P. W.·Ma, J.·Yuan, X.-B.
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Abstract

Katanin catalytic subunit A1 like 2 (KATNAL2) is a high-risk gene associated with autism spectrum disorders (ASD), however its impact on brain development and disease remains unclear. The present study revealed an unexpected role of KATNAL2 in regulating ependymal ciliary motion and cerebrospinal fluid flow during brain development, an important contributing factor for ASD. We discovered a distinct expression pattern of KATNAL2 in multiciliated ependymal cells of both human and mouse brains. Notably, an ASD-associated mutation of Katnal2 disrupted its molecular function and resulted in ASD-related behavioral deficits in mice. Additionally, this mutation affected the polarized organization and beating of ependymal cilia, leading to delayed cerebrospinal fluid flow and sustained ventricular enlargement from the early postnatal stage. Conditional ablation of Katnal2 specifically in the ependymal cells of neonatal mice is sufficient to cause ventricular dilation, whereas no such effect was observed in adult mice. Our findings highlight the importance of ependymal motile cilia and hydrocephalus in ASD, offering insights into its pathogenesis and potential intervention.

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Qiu, S., Cao, H., Xue, Y., Zhao, W., Xie, S., Wu, N., Song, M., Pan, Y.-H., Baas, P. W., Ma, J., Yuan, X.-B.. 2023-07-03. ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus. https://doi.org/10.1101/2023.07.03.547302

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