TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation

Neuron. 2017 Jan 18;93(2):379-393. doi: 10.1016/j.neuron.2016.12.006. Epub 2017 Jan 5.

Abstract

Abnormalities in dendritic spines are manifestations of several neurodevelopmental and psychiatric diseases. TAOK2 is one of the genes in the 16p11.2 locus, copy number variations of which are associated with autism and schizophrenia. Here, we show that the kinase activity of the serine/threonine kinase encoded by TAOK2 is required for spine maturation. TAOK2 depletion results in unstable dendritic protrusions, mislocalized shaft-synapses, and loss of compartmentalization of NMDA receptor-mediated calcium influx. Using chemical-genetics and mass spectrometry, we identified several TAOK2 phosphorylation targets. We show that TAOK2 directly phosphorylates the cytoskeletal GTPase Septin7, at an evolutionary conserved residue. This phosphorylation induces translocation of Septin7 to the spine, where it associates with and stabilizes the scaffolding protein PSD95, promoting dendritic spine maturation. This study provides a mechanistic basis for postsynaptic stability and compartmentalization via TAOK2-Sept7 signaling, with implications toward understanding the potential role of TAOK2 in neurological deficits associated with the 16p11.2 region.

Keywords: Septin7; TAOK2; chemical genetics; dendritic spine; kinase signaling; neurodevelopment; postsynaptic stability.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Compartmentation
  • Dendritic Spines / metabolism*
  • Disks Large Homolog 4 Protein
  • Gene Knockdown Techniques
  • Hippocampus / cytology
  • Hippocampus / embryology*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mass Spectrometry
  • Membrane Proteins / metabolism*
  • Microscopy, Confocal
  • Neurogenesis / genetics*
  • Phosphorylation / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Septins / metabolism*

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Protein-Serine-Threonine Kinases
  • TAO2 protein, rat
  • Sept7 protein, rat
  • Septins
  • Calcium