Nerve Growth Factor (NGF) is the prototypic and best studied member of the Neurotrophin family of neuronal growth factors, which are required for the survival and maintenance of many neuronal populations throughout the peripheral and central nervous systems. The principal mode of NGF signaling occurs over long distances, and has been postulated to occur by internalization and retrograde transport of an NGF-receptor complex within a """"""""signaling endosome"""""""" from the nerve terminal to the cell body. The process by which the endosome is formed and trafficked, as it relates to intracellular signaling, has remained largely intractable due to a lack of understanding of the mechanism of internalization and tools with which to manipulate the endosome. We have discovered, through our recent identification of a protein we term """"""""Pincher,"""""""" the means to attack this important problem. Pincher mediates the formation of an endosome from which NGF mediates long-term signaling. Our preliminary findings suggest a model whereby signals emanating from the signaling endosome are fundamentally different from those generated at the plasma membrane, permitting differential signaling during and after retrograde transport to the cell body. To further explore and extend this model, we propose two specific aims: (1) to determine the relative importance of the differential signaling pathways mediated by NGF at the plasma membrane vs. the endosome and (2) to elucidate the process by which Pincher forms and trafficks signaling endosomes. Our proposed studies are intended to elucidate the mechanism by which Neurotrophins such as NGF regulate neuronal phenotype and survival. Neuronal death and defective phenotypic function are the major causes of nervous system disorders such as those seen in Parkinson's and Alzheimer's diseases, stroke, and peripheral neuropathies. Our work addresses these diseases of the nervous system, in which 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 herein is essential to the rational design of therapeutics for combating these 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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