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Spatial and temporal differences between the trafficking of members of the neurotrophin family of proteins

Authors
Publisher
McGill University
Publication Date
Keywords
  • Biology
  • Neuroscience.
Disciplines
  • Biology

Abstract

The neurotrophin family of proteins regulates a wide variety of functions in neurons, including regulation of neuronal survival, axonal and dendritic growth and synaptic plasticity. The regulation of neurotrophin trafficking is believed to be important in many aspects of their function, as exemplified by the role of BDNF, which is released in response to activity, in long-term potentiation in the hippocampus and the ability of neurotrophins to initiate a retrograde pro-survival signal along peripheral axons. In this thesis I describe three mechanisms by which neurotrophin trafficking occurs differently for different members, or forms, of the neurotrophin family. Firstly, I show that two neurotrophins, BDNF and NT-4, which signal through the same receptors, can be released from cells containing both constitutive and regulated secretory pathways through different mechanisms. NT-4 is released continuously, soon after its synthesis, from AtT-20 cells, while BDNF is stored within the cells and released in response to depolarisation. Secondly, I show that, in primary sympathetic neurons, the functionally antagonistic Trk and p75NTR receptors, in complexes with their respective neurotrophin ligands, are differently localized on the cell surface and are internalized with different characteristics. This contradicts a model in which the antagonism between these receptors is mediated directly and instead suggests an indirect mechanism of antagonism. In addition, I show that the p75NTR-ligand complex can be retrogradely transported at a similar rate to that reported for Trk, but that the initiation of this transport occurs through a different mechanism. Finally, I show that the neurotrophin precursor, pro-BDNF, can be released endogenously from glial cells, consistent with its postulated role as a high affinity ligand for a p75NTR-containing signalling complex. When over-expressed in cell lines, pro-BDNF release is activity-independent, in contrast to

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