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 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.