The knockout of Moesin leads to excess microglia-mediated synaptic pruning and impairs social novelty in a mouse model
Genome-wide association studies (GWASs) have implicated a noncoding antisense RNA designated as MSNP1AS (Moesin pseudogene 1, antisense) in susceptibility to autism spectrum disorders (ASDs). MSNP1AS binds to and downregulates the Moesin (Msn) transcript and is highly overexpressed in the postmortem cerebral cortex of individuals with ASDs. However, the mechanistic link between Msn loss in vivo and ASD-related phenotypic traits remains enigmatic. Here, we generate Msn knockout (KO) mice, on which neurobehavioral tests reveal impaired social novelty and repetitive behaviors. Msn KO activates the microglial population, leading to aberrant C1q-dependent synaptic pruning followed by synaptic deficits in the medial prefrontal cortex. The aberrant regulatory pathway can be rescued by IFNAR1 antibody, which rescues microglial abnormalities and social deficits. Taken together, the results of the current study reveal a pathway in which Msn mediates interferon signaling and synaptic pruning to affect ASD-like behaviors, providing a functional genetic link between MSN and neurobehavioral abnormalities.
Authors
- Charlly Kao
- Wanjing Lai (ORCID: https://orcid.org/0000-0001-6123-7181)
- Jubao Duan (ORCID: https://orcid.org/0000-0002-7215-3220)
- Qingpei Chen
- Zhihua Luo (ORCID: https://orcid.org/0000-0001-8891-2765)
- Lingling Shi (ORCID: https://orcid.org/0000-0003-4225-209X)
- Yunbo Jiang
- Kwok‐Fai So (ORCID: https://orcid.org/0000-0003-4039-4246)
- You‐Qiang Song (ORCID: https://orcid.org/0000-0001-9407-2256)
- Yaxuan Wang
- Fang Li (ORCID: https://orcid.org/0000-0002-7617-6534)
- Li Zhang (ORCID: https://orcid.org/0000-0003-1489-0879)
- Kai You Wang (ORCID: https://orcid.org/0000-0002-6170-4744)
- Hongyao Zhu (ORCID: https://orcid.org/0009-0009-6961-3642)
- Yimei Niu
- Junlin Chen (ORCID: https://orcid.org/0000-0003-1878-9559)
- Yu Hu (ORCID: https://orcid.org/0009-0002-7180-5378)
Institutions
- Children's Hospital of Philadelphia (US)
- NorthShore University HealthSystem (US)
- Jinan University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1016/j.celrep.2025.116012
- Citations
- 1
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.84
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Project 211
- Key Technologies Research and Development Program of Guangzhou