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. Significance Statement Abnormal motor behavior is a hallmark of many neurological and psychiatric disorders and a common symptom across numerous diseases. Growing evidence highlights the critical role of the motor system in elucidating the pathophysiology and treatment of mental disorders. Digging behavior—a movement characterized by forefeet scratching and/or hindfeet substrate kicking—is poorly understood at the genetic level. Here, we identify FAT Atypical Cadherin 2 (FAT2) as a binding partner of Cbln1, a synaptic organizer for cerebellar parallel fiber synapses. We demonstrate that deletion of cerebellar granule cell FAT2 impairs synaptic integrity and motor behaviors. These findings establish FAT2 as essential for synaptic integrity and the execution of fine motor and digging behaviors.