Abstract
ABSTRACTIn the course of peripheral nerve regeneration, axons encounter different extracellular growth factors secreted by non‐neuronal cells at the injury site and retrogradely transported after binding to neuronal membrane receptor tyrosine kinases. The present study reviews the role of receptor transport in peripheral axon outgrowth and provides novel data on trafficking of fibroblast growth factor receptor type 1 (FGFR1). Differences in receptor transport are determined by different numbers of lysine residues acting as ubiquitination sites in the intracellular receptor domain. We previously demonstrated that overexpression of mutant FGFR1‐25R (25 out of 29 intracellular lysines replaced with arginine) results in enhanced receptor recycling as compared to wild‐type FGFR1 followed by strong stimulation of elongative axon growth in vitro. Here, the effects of lysine‐deficient FGFR1 (FGFR1‐29R lacking all 29 cytoplasmic lysine residues) or of only 15 lysine mutations (FGFR1‐15R) on axon outgrowth and concomitant changes in signal pathway activation were investigated by immunocytochemistry and morphometry of cultured primary neurons. Overexpression of FGFR1‐15R in adult sensory neurons resulted in enhanced receptor recycling, which was accompanied by increased axon elongation without stimulating axon branching. By contrast, FGFR1‐29R was neither endocytosed nor axon outgrowth affected. Although overexpression of FGFR1‐15R or FGFR1‐25Ra strongly promoted elongation, we did not detect increased signal pathway activation (ERK, AKT, PLC, or STAT3) in neurons expressing mutant FGFR1 as compared with wild‐type neurons raising the possibility that other signaling pathways or signaling independent mechanisms may be involved in the axon outgrowth effects of recycled FGF receptors. Anat Rec, 302:1268–1275, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
Highlights
Peripheral nerve regeneration is strongly influenced by neurotrophic factors and cytokines (Klimaschewski et al, 2013)
This prompted us to investigate the effects of fibroblast growth factor receptor type 1 (FGFR1)-15R comprising 15 mutated lysine residues to test our hypothesis that enhanced recycling but not the number of lysines is responsible for this effect
The total axonal length and the maximal length of the longest axon were strongly enhanced compared with FGFR1-WT with or without fibroblast growth factor (FGF)-2 indicating at least partial autoactivation of FGFR1-15R upon overexpression
Summary
Peripheral nerve regeneration is strongly influenced by neurotrophic factors and cytokines (Klimaschewski et al, 2013). Growth factors are expressed mainly by Schwann cells and activate receptor tyrosine kinases (RTKs) present at the axonal plasma membrane. Neurotrophins such as nerve growth factor (NGF) or brain derived neurotrophic factor (BDNF) are released from dedifferentiating Schwann cells in the distal nerve stump after transection. They bind to their cognate high-affinity receptors, are internalized by endocytosis, and are transported retrogradely via early and late endosomes. These contribute significantly to elongative axon regeneration at least in vitro (Ascano et al, 2012; Klimaschewski et al, 2013)
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