Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling

Dev Cell. 2015 Jun 22;33(6):690-702. doi: 10.1016/j.devcel.2015.04.009. Epub 2015 May 21.


Recent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase δ (PTPδ); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Corpus Striatum / metabolism
  • Endosomes / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Protein Binding
  • Protein Transport
  • Receptor, trkB / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism
  • Signal Transduction
  • rab GTP-Binding Proteins / metabolism


  • Brain-Derived Neurotrophic Factor
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Slitrk5 protein, mouse
  • Receptor, trkB
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2
  • rab11 protein
  • rab GTP-Binding Proteins