Endocytosis and transport of growth factor receptors in peripheral axon regeneration: Novel lessons from neurons expressing lysine deficient FGF receptor type 1 in vitro.

In 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. (c) 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.