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, Fat2 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.