Abstract
BDNF/TrkB signaling plays critical roles in axonal outgrowth of neurons, the process of which requires the remodeling of the cytoskeleton structure, including microtubules and filamentous actin. However, the mechanism by which BDNF/TrkB signaling regulates cytoskeleton reorganization is still unclear. Here, we identified a novel interaction between LIMK1 and TrkB, which is required for the BDNF-induced axonal elongation. We demonstrated that BDNF-induced TrkB dimerization led to LIMK1 dimerization and transphosphorylation independent of TrkB kinase activity, which could further enhance the activation and stabilization of LIMK1. Moreover, activated LIMK1 translocated to the membrane fraction and phosphorylated its substrate cofilin, thus promoting actin polymerization and axonal elongation. Our findings provided evidence of a novel mechanism for the BDNF-mediated signal transduction leading to axonal elongation.
Highlights
BDNF promotes axonal outgrowth, whereas the underlying molecular mechanism has remained unclear
Because of the expression of p75 neurotrophin receptor (p75NTR) and TrkB isoform 1 (T1) in hippocampal neurons, we examined the interaction between the overexpressed HA-LIMK1 and FLAGp75NTR or FLAG-T1
We found that up-regulation of LIMK1 levels increased axonal length whereas Small interfering RNAs (siRNAs) knocking down LIMK1 levels decreased axonal length, the results of which are in conformity with previous studies [20, 22], and BDNF treatment could significantly promote axonal elongation
Summary
BDNF promotes axonal outgrowth, whereas the underlying molecular mechanism has remained unclear. BDNF/TrkB signaling plays critical roles in axonal outgrowth of neurons, the process of which requires the remodeling of the cytoskeleton structure, including microtubules and filamentous actin. BDNF/ TrkB signaling plays an important role in axonal outgrowth through actin dynamics and microtubule assembly regulation [14], the underlying molecular mechanism has remained unclear. A growing body of evidence suggests that both BDNF/TrkBand LIMK1/cofilin-regulated actin dynamics are involved in growth cone motility, neurite extension, synaptogenesis, and. TrkB/LIMK1 Interaction Contributes to Axonal Elongation long term potentiation in neurons (24 –27), which leads us to hypothesize that there may exist cross-talk between BDNF/ TrkB and LIMK1/cofilin pathways. We present evidence that LIMK1 could directly bind to TrkB, and BDNF treatment could induce LIMK1 activation and stabilization, which facilitate axonal outgrowth in hippocampal neurons
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