Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling

Abstract

Summary Recent studies in humans and in genetic mouse models have identified 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 BDNF-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a trans-synaptic binding partner, 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 the recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling.

Kalirin is required for BDNF-TrkB stimulated neurite outgrowth and branching

“…The time course observed for TrkB activation in WT hippocampal neurons was consistent with published studies monitoring the same sites (Ji et al, 2010; Lai et al, 2012). Retardation of TrkB recycling (via Rab11-positive endosomes) is also seen in Slitkr5 knockout neurons (Song et al, 2015). …”

“…4, 6]. The regulated endocytosis of many receptors, including TrkB, is crucial to normal cortical development (Song et al, 2015; Yap and Winckler, 2015). The role of the natural truncated variant TrkB.T1, which lacks the kinase domain and becomes the dominant TrkB protein in the adult (Fenner, 2012), has not been investigated here, nor have the changes in NMDA signaling that occur within 2 minutes of TrkB activation by BDNF (Levine et al, 1998).…”

Transcriptomic Profiling Discloses Molecular and Cellular Events Related to Neuronal Differentiation in SH-SY5Y Neuroblastoma Cells

“…Interestingly, another member of this family, SLITRK3, was found differentially expressed in RA-NBM cells and linked to neuritogenesis annotation (Online Resource ESM10). Recently, SLITRK5 was shown to modulate BDNF-dependent biological responses by regulating TrkB receptor recycling (Song et al 2015). Whether the increased expression of SLITRK6/SLITRK6 observed in this experimental setting (Fig.…”

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

“…The LRR protein, Linx, was identified as a TrkA interactor able to increase TrkA signaling in developing sensory neurons and to facilitate NGFinduced axonal extension and target tissue innervation [42]. In addition, a recent study shows that another LRR-containing protein, Slitrk5, facilitates BDNF-induced TrkB signaling and biological responses to BDNF in GABAergic striatal neurons [49]. In contrast to these two LRR proteins, here we found that Lrig1 negatively regulates BDNF-induced TrkB signaling required to hippocampal dendrite development.…”

“…In particular, these proteins physically interact with RTKs to attenuate or promote neurotrophic factor receptor signaling in spatially and temporally controlled manners, acting at specific points after receptor engagement [25,37,49]. It has been proposed that these regulatory proteins containing LRR domains may have evolved not only to avoid signaling errors that could lead to aberrant neuronal physiology but also to increase the repertoire of neurotrophic growth factor receptor signaling intensities and biological effects.…”