CNTF specifically slows down the axonal transport of signalling endosomes

Abstract

Efficient axonal transport is essential for maintaining neuronal function, enabling the bidirectional delivery of diverse cargoes between the cell body and distal compartments. In the neuromuscular system, neurotrophic factors (NTFs) regulate motor neuron survival, function, and synaptic connectivity, in part, through retrograde trafficking of activated NTF-receptor complexes from the neuromuscular junction (NMJ) to the cell body. We recently demonstrated that brain-derived neurotrophic factor (BDNF) stimulation to muscles selectively enhances retrograde transport of signalling endosomes in fast, but not slow, motor neurons in vivo. Moreover, both axonal endosome transport and its BDNF-mediated regulation are disrupted in mouse models of diseases impacting motor neurons. Here, we examined whether additional NTFs, when applied to distal axon terminals, share this transport-modulating property. Through imaging sciatic nerves in anaesthetised mice, we tracked the in vivo dynamics of signalling endosomes in fast (FMN) and slow motor neurons (SMN) via intramuscular injections of a fluorescently conjugated, atoxic fragment of tetanus neurotoxin (HCT). HCT was co-administered with ciliary neurotrophic factor (CNTF), hepatocyte growth factor (HGF), neurturin (NRTN), or proBDNF - four growth factors with known effects on motor neurons. Compared to vehicle-treated controls, proBDNF, HGF, and NRTN, produced no detectable change in transport dynamics. In contrast, CNTF markedly reduced endosome speeds in both FMNs and SMNs, indicating remarkable selectivity of specific NTFs in the regulation of signalling endosome transport in motor neurons. Understanding this selectivity may aid the development of muscle-targeted NTF-based therapeutic strategies aimed at restoring axonal transport in neurodegenerative disease, peripheral neuropathy, and nerve injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/681259v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10e4229org.highwire.dtl.DTLVardef@119c69aorg.highwire.dtl.DTLVardef@13dd629org.highwire.dtl.DTLVardef@b733ec_HPS_FORMAT_FIGEXP M_FIG C_FIG