Coordinated nuclear and synaptic shuttling of afadin promotes spine plasticity and histone modifications

Jon Eric Van Leeuwen, Igor Rafalovich, Katherine Sellers, Kelly A. Jones, Theanne N. Griffith, Rafiq Huda, Richard J. Miller, Deepak P. Srivastava*, Peter Penzes

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 NMDAreceptor 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.

Original languageEnglish (US)
Pages (from-to)10831-10842
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number15
DOIs
StatePublished - Apr 11 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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