Long distance retrograde signaling from nerve endings to the soma is required for Neurotrophin-mediated cell survival and the control of neuronal phenotype. Despite its great importance, fundamental questions about this signaling process, which involves formation and transport of signaling endosomes, remain unresolved. Some issues are highly contested, such as how persistent, long-distance signaling can be achieved by an endosome-based system. A potential resolution was provided recently by our lab that pointed to involvement of a novel, specialized endocytotic pathway for neurotrophins and their Trk receptors. Dissecting this newly identified Neurotrophin/Trk signaling pathway and its role in retrograde axonal signaling is the primary focus of this grant. At the heart of this signaling pathway is the novel protein Pincher (Pinocytic Chaperone) identified in our lab. Pincher mediates the primary retrograde signaling pathway for NGF and the other neurotrophin Trk receptors, but not other receptor tyrosine kinases. EGF for example, which unlike NGF does not mediate long-distance neuronal survival, utilizes the classic short-lived, clathrin-mediated endosomal pathway that is Pincher-independent. We plan to definitively show that the EGF and NGF signaling pathways are distinct at the level of endosomes and, further, to identify the Pincher-associated proteins that account for these differences. To achieve this goal we propose three specific aims: (1) Identify the molecular components, and their functional roles, in Pincher/TrkA endosomes in the cell soma (2) Identify the molecular blueprint of Pincher/Trk endosomes at distinct stages in the retrograde transport pathway (3) Determine the relative contributions of clathrin and Pincher associated proteins to neuronal survival. Our studies are directly relevant to both Down's syndrome and Alzheimer's disease, wherein retrograde trophic support is defective and/or restoration of such support can be therapeutic in preventing neuronal loss and dysfunction. An understanding of the mechanisms for trophic factor signaling and delivery as proposed is essential to the rational design of therapeutics for combating these and other related diseases.
| Philippidou, Polyxeni; Valdez, Gregorio; Akmentin, Wendy et al. (2011) Trk retrograde signaling requires persistent, Pincher-directed endosomes. Proc Natl Acad Sci U S A 108:852-7 |
| Harrington, Anthony W; St Hillaire, Coryse; Zweifel, Larry S et al. (2011) Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146:421-34 |
| Joset, Armela; Dodd, Dana A; Halegoua, Simon et al. (2010) Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling. J Cell Biol 188:271-85 |
| Bonanomi, Dario; Fornasiero, Eugenio F; Valdez, Gregorio et al. (2008) Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones. J Cell Sci 121:3757-69 |
| Valdez, Gregorio; Philippidou, Polyxeni; Rosenbaum, Julie et al. (2007) Trk-signaling endosomes are generated by Rac-dependent macroendocytosis. Proc Natl Acad Sci U S A 104:12270-5 |
| Boykevisch, Sean; Zhao, Chen; Sondermann, Holger et al. (2006) Regulation of ras signaling dynamics by Sos-mediated positive feedback. Curr Biol 16:2173-9 |
| Valdez, Gregorio; Akmentin, Wendy; Philippidou, Polyxeni et al. (2005) Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. J Neurosci 25:5236-47 |
| Wang, Sheng; Liu, Yan; Adamson, Crista L et al. (2004) The mammalian exocyst, a complex required for exocytosis, inhibits tubulin polymerization. J Biol Chem 279:35958-66 |
| Kuruvilla, Rejji; Zweifel, Larry S; Glebova, Natalia O et al. (2004) A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118:243-55 |
| Shao, Yufang; Akmentin, Wendy; Toledo-Aral, Juan Jose et al. (2002) Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J Cell Biol 157:679-91 |
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