Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice

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Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.
Publisher
PUBLIC LIBRARY SCIENCE
Issue Date
2024-05
Language
English
Article Type
Article
Citation

PLOS BIOLOGY, v.22, no.5

ISSN
1544-9173
DOI
10.1371/journal.pbio.3002596
URI
http://hdl.handle.net/10203/319738
Appears in Collection
MSE-Journal Papers(저널논문)BS-Journal Papers(저널논문)
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