The Role of Neurotrophins in Axonal Growth, Guidance, and Regeneration

Abstract

Neurotrophins are proteins that regulate neuronal survival, axonal growth, synaptic plasticity and neurotransmission. They are members of the neurotrophic factors family and include factors such as the nerve growth factor (NGF), the brain derived neurotrophic factor (BDNF), the neurotrophin-3 (NT-3), and the neurotrophin-4/5 (NT-4/5). These molecules bind to two types of receptors: i) tyrosine kinase receptors (TrkA, TrkB, TrkC) and ii) a common neurotrophin receptor (p75NTR). The two receptor types can either suppress or enhance each other's actions. Neurotrophins have a multifunctional role both in the central and peripheral nervous system. They have been suggested as axonal guidance molecules during the growth and regeneration of nerves. It has also been proven that they stimulate axonal growth by mediating the polymerization and accumulation of F-actin in growth cones and axon shafts. Neurotrophins, as other neurotrophic factors, have been shown that they reduce neuronal injury by exposure to excitotoxins, glucose deprivation, or ischemia. Furthermore, the nerve regeneration promoting effect of these growth factors is well documented for many different models of central or peripheral nervous system injury. Several studies have shown that exogenous administration of these factors has protective properties for injured neurons and stimulates axonal regeneration. Based on these properties, these molecules may be used as therapeutic agents for treating degenerative diseases and traumatic injuries of both the central and peripheral nervous system.

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

“…Given the vital role of NGF in neuronal differentiation into the cholinergic phenotype [5,19,36], adverse effects on ngfg expression may contribute to the particular sensitivity of these neurons to organophosphates [4,42,72,73]. Similarly, BDNF plays critical roles in neuronal cell differentiation, brain development and synaptic plasticity [51], and alterations in this trophic factor have been implicated in psychiatric diseases, neurodegenerative disorders and epilepsy [34,35,44,67,68,83].…”

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

“…Note that the mice in these experiments were from a Bax WT background to enable direct comparison with the original PTEN deletion data (Park et al, 2008); however, this means that possible survivalpromoting effects of the mutant alleles cannot be excluded. The extent of regeneration achieved by direct genetic activation of specific intracellular signaling pathways, including B-RAF, DLK, PI3-kinase-mTOR, KLF, and JAK-STAT pathways Yan et al, 2009;Park et al, 2010;Blackmore et al, 2012;Shin et al, 2012;Lang et al, 2013), compares favorably with what has been reported for application of growth factors such as NGF, BDNF, GDNF, and CNTF (Lykissas et al, 2007;Zhang et al, 2009;Allen et al, 2013;Leibinger et al, 2013). Growth factors as promoters of regeneration are hobbled by two major issues.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…P75 NTR was discovered as one of two receptors able to bind nerve growth factor (Chao et al, 1986), the other being TrkA . TrkA was rapidly shown to mediate the known responses to NGF, such as neurite outgrowth and neuronal survival (Lee et al, 2001a;Lykissas et al, 2007), whereas the precise biological role of p75 NTR remained misunderstood. p75 NTR was shown to collaborate with TrkA to form high-affinity sites for NGF binding (Hempstead et al, 1991).…”