Paxillin: From Cell Adhesion to Nuclear Splicing Regulator in Neurons

New research published in The EMBO Journal uncovers an unexpected nuclear role for paxillin, a protein previously known for regulating cell adhesion and migration. Chu and colleagues demonstrate that activity-dependent phosphorylation of paxillin at serine 119 (p-PaxillinS119) drives its nuclear translocation in developing neurons, where it fine-tunes alternative splicing (AS) of synaptic genes during critical periods of brain development.

During early postnatal life, neuronal circuits are refined based on sensory input—a process crucial for learning and memory. The study shows that NMDA receptor activation or sensory stimulation triggers S119 phosphorylation, allowing paxillin to enter the nucleus via importin-β2. Once inside, it localizes to nuclear speckles, interacting with RNA-binding proteins like U2AFs, FUS, and NOVA1/2, modulating AS of key synaptic genes such as Snap25. This switching of isoforms supports presynaptic function and synaptic plasticity.

Disruption of S119 phosphorylation in mice leads to delayed Snap25 isoform switching, impaired hippocampal synaptic transmission, and short-term memory deficits, underscoring paxillin’s essential role in linking neuronal activity to genomic responses.

This work expands paxillin’s known repertoire beyond cytoskeletal regulation, highlighting adhesion proteins as versatile nuclear regulators. The findings have broader implications for neurodevelopmental disorders, including autism and schizophrenia, where splicing dysregulation during critical periods contributes to disease. Targeting paxillin phosphorylation could offer therapeutic avenues for enhancing plasticity or mitigating cognitive decline.