Atypical Cadherin FAT2 Is Required for Synaptic Integrity and Motor Behaviors

In humans, mutations or deletions of atypical FAT cadherin genes are linked to autism spectrum disorder and cerebellar ataxia. However, their large genomic size and the enormous size of their encoded proteins have hampered functional studies, leaving the roles of FAT cadherins poorly understood. To address this gap, we investigated FAT2-an atypical cadherin selectively expressed in cerebellar granule cells-in murine cerebellar function. We demonstrate that FAT2 directly binds Cbln1, a secreted molecule essential for synapse formation and plasticity at Purkinje cell synapses. Furthermore, <i>Fat2</i> deletion mice of both sexes selectively weakened the synaptic strength of parallel fiber synapses in the cerebellum and impaired motor behaviors. These findings reveal that FAT2 is indispensable for motor behaviors, likely through regulating Cbln1-dependent synaptic integrity.

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Publication Details

Journal
Journal of Neuroscience
Published
2025-05-20
DOI
https://doi.org/10.1523/jneurosci.2345-24.2025
Citations
4
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
4.61

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article

Atypical Cadherin FAT2 Is Required for Synaptic Integrity and Motor Behaviors

Xiankun Wang, Yongfei Cui, Markus Wöhr, Yonglin Pu et al.
4 citations
Journal of Neuroscience
Hippo pathway signaling and YAP/TAZ
4.61
article

Atypical Cadherin FAT2 Is Required for Synaptic Integrity and Motor Behaviors

Xiankun Wang, Yongfei Cui, Markus Wöhr, Yonglin Pu, Jifei Miao, Bo Zhang, Jun Wang, Lei Guan, Lixin Xie, Liming Qin, Ying Han
article en
4 citations

Abstract

In humans, mutations or deletions of atypical FAT cadherin genes are linked to autism spectrum disorder and cerebellar ataxia. However, their large genomic size and the enormous size of their encoded proteins have hampered functional studies, leaving the roles of FAT cadherins poorly understood. To address this gap, we investigated FAT2-an atypical cadherin selectively expressed in cerebellar granule cells-in murine cerebellar function. We demonstrate that FAT2 directly binds Cbln1, a secreted molecule essential for synapse formation and plasticity at Purkinje cell synapses. Furthermore, <i>Fat2</i> deletion mice of both sexes selectively weakened the synaptic strength of parallel fiber synapses in the cerebellum and impaired motor behaviors. These findings reveal that FAT2 is indispensable for motor behaviors, likely through regulating Cbln1-dependent synaptic integrity.

Journal of NeuroscienceVol. 45(24)
Allen Institute for Brain Science (US), Philipps University of Marburg (DE), Shenzhen University (CN), Peking University (CN), Shenzhen Bay Laboratory (CN), VIB-KU Leuven Center for Brain & Disease Research (BE), Shenzhen Academy of Aerospace Technology (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, Fonds Wetenschappelijk Onderzoek
Good health and well-being
Openalex Percentile: Top 6%
Hippo pathway signaling and YAP/TAZ
4.61
DOIOpen Access PDFOpenAlex
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