23 - Trophic factors and their influence on regeneration

Summary

Developing neurons in both the central and peripheral nervous system face many challenges. They must migrate to their proper location, extend an axon towards their correct post-synaptic targets and survive a period of naturally occurring cell death. The neurotrophic hypothesis, a basic tenet of developmental neurobiology, states that as developing neurons extend axons to their target tissues, their survival becomes dependent on soluble factors released from the target tissues in limiting amounts. After injuries that sever axons, the damaged neurons face many of the same problems as developing axons, that is they must survive, extend an axon, and if function is to be restored, make synapses with correct target cells. Consequently, it has often been suggested that supplying exogenous neurotrophins (NTs) might have therapeutic value after traumatic injury to the nervous system. In this chapter, we review the biology of NTs and their receptors with an emphasis on their use to encourage nerve regeneration after damage to both the central and peripheral nervous system.

NT family and receptors

NTs are secreted growth and differentiation factors that bind directly to receptor complexes on their target cells and exert multiple downstream effects. The NT family consists of four highly conserved proteins that are found in all mammalian species: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4). NTs are synthesized as proproteins that are cleaved intracellularly by furin proteases to generate the mature 13.5-kDa protein (for review, see Teng and Hempstead, 2004).