Chapter 312 - The Neurotrophin Factors

Abstract

This chapter examines the mechanisms of action of neurotrophic factors. Neurotrophic growth factors are proteins responsible for cell survival, proliferation, migration, neurite elongation, neurotransmitter expression, and synaptic maturation in the nervous system. Early in neuronal development of the sympathetic nervous system there is an overproduction of precursor sympathetic neurons, sympathicoblasts, which, when exposed to the nerve growth factor protein (NGF) in the absence of glucocorticoids, extend neurites oriented to the NGF source. Over time there is a decrease in the ambient levels of NGF even as the extended growth cones contact target tissues that synthesize and release the reduced amounts of NGF. Synaptic contact between the neuronal growth cones that display NGF receptors takes place, and there is binding of nearby NGF molecules to these receptors followed by internalization and the eventual retrograde transport to the neuronal soma of both encapsulated NGF-receptor complexes and activated NGF receptors. The overproduction of neurons early in development is followed by a significant decrease in their number as maturity is reached. The initial event in the regulation of cell death by neurotrophins during development is the binding of a neurotrophin ligand to a neurotrophin receptor, and for the neurotrophin factors such as NGF, BDNF, NT-3, and NT4/5 and there are two categories of receptors that include p75NTR and the Trk receptors. The p75NTR binds pro-neurotrophin with a high affinity compared to the mature NTs. When p75NTR forms a complex with sortilin, it promotes neuronal cell death via binding to pro-neurotrophins; whereas when p75NTR forms a complex with NOGO-R-LINGO, it inhibits NOGO-dependent axonal growth as well as semaphorin 3 A axonal repulsion.