Coordinated Nuclear and Synaptic Shuttling of Afadin Promotes Spine Plasticity and Histone Modifications

• Published in: The Journal of biological chemistry Vol. 289; no. 15; pp. 10831 - 10842
• Main Authors: VanLeeuwen, Jon-Eric, Rafalovich, Igor, Sellers, Katherine, Jones, Kelly A., Griffith, Theanne N., Huda, Rafiq, Miller, Richard J., Srivastava, Deepak P., Penzes, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus; AF-6; Animals; Brain - embryology; Cell Biology; Cell Nucleus - metabolism; Chromatin Histone Modification; Cytosol - metabolism; Dendritic Spine; Dendritic Spines - metabolism; Gene Expression Regulation; GTP Phosphohydrolases - metabolism; Histones - metabolism; LIM Domain Proteins - metabolism; Microfilament Proteins - metabolism; Neurobiology; Neuronal Plasticity - physiology; Neurons - metabolism; Nucleus; Phosphorylation; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Signal Transduction; Signaling; Small GTPase; Synapses; Synapses - metabolism; Synaptic Plasticity; Chromatin Histone Modification; AF-6; Nucleus; Signaling; Synaptic Plasticity; Small GTPase; Neurobiology; Dendritic Spine; Synapses; Cell Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.536391

The ability of a neuron to transduce extracellular signals into long lasting changes in neuronal morphology is central to its normal function. Increasing evidence shows that coordinated regulation of synaptic and nuclear signaling in response to NMDA receptor activation is crucial for long term memory, synaptic tagging, and epigenetic signaling. Although mechanisms have been proposed for synapse-to-nuclear communication, it is unclear how signaling is coordinated at both subcompartments. Here, we show that activation of NMDA receptors induces the bi-directional and concomitant shuttling of the scaffold protein afadin from the cytosol to the nucleus and synapses. Activity-dependent afadin nuclear translocation peaked 2 h post-stimulation, was independent of protein synthesis, and occurred concurrently with dendritic spine remodeling. Moreover, activity-dependent afadin nuclear translocation coincides with phosphorylation of histone H3 at serine 10 (H3S10p), a marker of epigenetic modification. Critically, blocking afadin nuclear accumulation attenuated activity-dependent dendritic spine remodeling and H3 phosphorylation. Collectively, these data support a novel model of neuronal nuclear signaling whereby dual-residency proteins undergo activity-dependent bi-directional shuttling from the cytosol to synapses and the nucleus, coordinately regulating dendritic spine remodeling and histone modifications. Background: Coordinated synaptic and nuclear signaling is required for long lasting changes in neuronal morphology. Results: Afadin undergoes activity-dependent bi-directional shuttling to synapses and the nucleus resulting in dendritic spine remodeling and histone modifications. Conclusion: Afadin is required for coordinated signaling at synapses and the nucleus. Significance: Bi-directional trafficking of afadin is required for coordinated synaptic and nuclear signaling in response to activity-dependent stimulation.