Tubular microdomains of Rab7-endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth 2B.

Axonal survival and growth requires signalling from tropomyosin receptor kinases (Trks). To transmit their signals, receptor-ligand complexes are endocytosed and retrogradely trafficked to the soma where downstream signalling occurs. Vesicles transporting neurotrophic receptors to the soma are reported to be Rab7-positive late endosomes/multi vesicular bodies where receptors localize within so-called intraluminal vesicles. Therefore, one challenging question is how downstream signalling is possible given the insulating properties of intraluminal vesicles. In this study, we report that Rab7-endosomes/multi vesicular bodies retrieve TrkA through tubular microdomains. Interestingly, this phenotype is absent for the EGF-receptor. Further, we found that EndophilinA1, EndophilinA2 and EndophilinA3 together with WASH1 are involved in the tubulation process. In Charcot-Marie-Tooth 2B, a neuropathy of the peripheral nervous system, this tubulating mechanism is disrupted. In addition, the ability to tubulate correlates with the phosphorylation levels of TrkA as well as with neurite length in neuronal cultures from dorsal root ganglia. In all, we report a new retrieval mechanism of late Rab7-endosomes, which enables TrkA signalling and sheds new light onto how neurotrophic signalling is disrupted in CMT2B.