Acid Test

Science Signaling  16 Aug 2011:
Vol. 4, Issue 186, pp. ec224
DOI: 10.1126/scisignal.4186ec224

The neurotrophin receptor TrkA binds to nerve growth factor (NGF) and neurotrophin 3 (NT3) to activate extension of axons. However, only NGF triggers the formation of TrkA-containing signaling endosomes that are transported in a retrograde manner to the soma to promote neuronal survival. Harrington et al. found that stabilization of the actin cytoskeleton in mouse sympathetic neurons by jasplakinolide treatment prevented retrograde transport of TrkA endosomes, suggesting a requirement for actin depolymerization in this process. Higher amounts of the actin filament–severing protein cofilin associated with TrkA isolated from neurons treated with NGF compared with that from neurons treated with NT3. In addition, cofilin colocalized to a greater extent with TrkA endosomes in NGF-treated neurons than in those treated with NT3. Retrograde transport of TrkA endosomes was impaired in NGF-treated neurons expressing an shRNA directed against cofilin, an effect that was largely rescued by application of the actin-depolymerizing agent latrunculin A. More of the GTPase Rac1, which can enhance activation of cofilin, was activated and associated with TrkA endosomes in neurons treated with NGF compared with those treated with NT3. Expression of a dominant-negative form of Rac1 prevented retrograde transport of TrkA endosomes and their colocalization with cofilin in NGF-treated neurons, whereas expression of a constitutively active form of Rac1 enabled retrograde transport of TrkA endosomes and survival signaling in NT3-treated neurons. The ability of NT3 to bind to TrkA on PC12 cells was decreased if the culture medium was acidic, and manipulations that prevented endosome acidification in NT3-treated neurons resulted in retrograde transport of TrkA endosomes, colocalization of cofilin with TrkA endosomes, and activation of Rac1. Thus, NGF can promote survival signaling because, unlike NT3, it forms stable complexes with TrkA under acidic conditions, a property that enables this ligand to trigger TrkA-mediated signaling in endosomes, recruitment of actin-organizing proteins, and retrograde transport of TrkA endosomes.

A. W. Harrington, C. St. Hillaire, L. S. Zweifel, N. O. Glebova, P. Philippidou, S. Halegoua, D. D. Ginty, Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146, 421–434 (2011). [PubMed]