Impaired neurotrophin-3 signaling in a TrkAII mutant associated with hereditary polyneuropathy

Mutations of the neurotrophin receptor tyrosine kinase TrkA (NTRK1) cause congenital sensory neuropathy with insensitivity to pain and anhydrosis (CIPA), also called hereditary sensory and autonomous neuropathy type IV (HSAN IV). The neuronal splice variant of TrkA, TrkAII, binds two neurotrophin li...

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Bibliographic Details
Published in:Experimental neurology 2010-07, Vol.224 (1), p.318-320
Main Authors: Flohr, S., Ewers, P., Fink, G.R., Weis, J., Krüttgen, A.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Blotting, Western
Cells, Cultured
CIPA
Humans
Injuries of the nervous system and the skull. Diseases due to physical agents
Medical sciences
Mutation
Neurology
Neurotrophin
Neurotrophin 3 - genetics
Neurotrophin 3 - metabolism
NGF
NT3
p75
p75NTR
Phosphorylation
Polyneuropathy
Receptor, trkA - genetics
Receptor, trkA - metabolism
Signal Transduction - genetics
Traumas. Diseases due to physical agents
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Summary:Mutations of the neurotrophin receptor tyrosine kinase TrkA (NTRK1) cause congenital sensory neuropathy with insensitivity to pain and anhydrosis (CIPA), also called hereditary sensory and autonomous neuropathy type IV (HSAN IV). The neuronal splice variant of TrkA, TrkAII, binds two neurotrophin ligands, nerve growth factor (NGF) and neurotrophin-3 (NT3). Several studies have demonstrated NGF signaling defects in CIPA-associated TrkA mutants. To date, however, no study has examined NT3/TrkA signaling of CIPA mutants. As the interaction of NT3 and TrkA temporally and spatially precedes the interaction of NGF with TrkA, we examined the signaling of NT3 in a CIPA-associated TrkA mutant. Intriguingly, we revealed remarkable defects in NT3-induced ERK1/2 phosphorylation and neurite outgrowth. The impact of our findings is twofold. First, our data call for a re-examination of previously described TrkAII CIPA mutants regarding their NT3 signaling capability. Second, we envision that CIPA/HSAN IV polyneuropathies might fall into two different subgroups: one with diminished NT3/TrkAII signaling, in which axons actually do not reach their targets, and a second group with sufficient NT3/TrkAII signaling but diminished NGF/TrkAII signaling, in which axons do reach their targets, yet degenerate after successful target engagement.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2010.02.009