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- Title
Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice.
- Authors
Kang, Ryeonghwa; Kim, Kyungdeok; Jung, Yewon; Choi, Sang-Han; Lee, Chanhee; Im, Geun Ho; Shin, Miram; Ryu, Kwangmin; Choi, Subin; Yang, Esther; Shin, Wangyong; Lee, Seungjoon; Lee, Suho; Papadopoulos, Zachary; Ahn, Ji Hoon; Koh, Gou-Young; Kipnis, Jonathan; Kang, Hyojin; Kim, Hyun; Cho, Won-Ki
- Abstract
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. Mutations in the microtubule regulatory protein Katnal2 have been linked to autism. This study finds that loss of Katnal2 in mice leads to autism-related phenotypes, which are driven in part by altered ciliary function in the lateral ventricles.
- Subjects
PHENOTYPES; AUTISM spectrum disorders; CEREBRAL ventricles; TUBULINS; MICE
- Publication
PLoS Biology, 2024, Vol 22, Issue 5, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002596