title: Coordinated nuclear and synaptic shuttling of afadin promotes spine plasticity and histone modifications.
abstract: 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.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Jon-Eric
authors.initials: JE
authors.lastname: VanLeeuwen
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Igor
authors.initials: I
authors.lastname: Rafalovich
authors.affiliation: Department of Neuroscience and Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sellers
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Theanne N
authors.initials: TN
authors.lastname: Griffith
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Rafiq
authors.initials: R
authors.lastname: Huda
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Neuroscience and Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom. Electronic address: deepak.srivsatava@kcl.ac.uk.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Srivastava
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611. Electronic address: p-penzes@northwestern.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001921:Brain / Q000196:embryology; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism*
chemical_list: C507006:Afdn protein, rat; D006657:Histones; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D020558:GTP Phosphohydrolases
keywords: AF-6; Cell Biology; Chromatin Histone Modification; Dendritic Spine; Neurobiology; Nucleus; Signaling; Small GTPase; Synapses; Synaptic Plasticity