Neurotrophin Signaling: A New Perspective
Wednesday, Oct 17, 2012, 8:30 AM - 9:40 AM
Biozentrum, Univ. of Basel, Switzerland, Basel, Switzerland
Neurotrophins and their receptors have emerged as a small group of signaling molecules affecting most aspects of neuronal function in vertebrates. While their absence in C. elegans and D. melanogaster is a complicating factor, this is nonetheless worth noting in the context of elaborate brain functions. These include for example memory in humans, with the discovery of a link between memory retention and a polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF; Egan et al. 2003 Cell 112, 257-269). This followed early reports in rodents indicating a role for BDNF in long-term potentiation and other highly relevant studies indicating that the expression of its gene is regulated by neuronal activity. While the very low abundance of BDNF remains a challenge with regard to its biochemistry and cell biology in the brain, we recently managed to localize it together with its cleaved pro-peptide to pre-synaptic large dense core vesicles (Dieni et al., 2012, J. Cell Biol. in press). In the context of neurotrophin signaling, this pre-synaptic localization is somewhat surprising in the face of studies with nerve growth factor (NGF) in the peripheral nervous system, the results of which have profoundly influenced the thinking in the field. In particular, the retrograde mode of action of NGF is a specially attractive feature of its biology as it convincingly explains the ability of peripheral tissues to regulate their degree of innervation by preventing the death of NGF-dependent neurons. Using neurons differentiated from engineered embryonic stem cells, we recently realized that this NGF-dependency for survival is actually a consequence of the expression of its receptor TrkA (Nikoletopoulou et al., 2010 Nature 467, 59-63). A re-analysis of the corresponding mouse mutants confirmed this result which indicates that neurons are intrinsically programmed to be eliminated during development. While the closely related receptor TrkC also causes cell death, the third member of the family, the BDNF receptor TrkB, does not kill neurons. This is also relevant as most CNS neurons express TrkB, but do not depend for survival on TrkB ligands during normal development. It thus appears that the close structural relatedness of neurotrophins and of their Trk receptors only allows limited predictions to be made as to their functions in the nervous system.
Swiss National Foundation
[Authors]. [Abstract Title]. Program No. XXX.XX. 2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2012. Online.
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