Several proteins have been identified that are necessary for survival and growth of neurons. Some of these neurotrophins are products of the muscles or other structures that the neurons innervate, but many in the CNS are produced by astrocytes. These proteins bind to receptors at the endings of a neuron. They are internalized and then transported by retrograde transport to the neuronal cell body, where they foster the production of proteins associated with neuronal development, growth, and survival. Other neurotrophins are produced in neurons and transported in an anterograde fashion to the nerve ending, where they maintain the integrity of the postsynaptic neuron.
The first neurotrophin to be characterized was NGF, a protein growth factor that was found to be necessary for the growth and maintenance of sympathetic neurons and some sensory neurons. It is present in a broad spectrum of animal species, including humans, and is found in many different tissues. Compared to female mice, male mice have a very high concentration of NGF in their submandibular salivary glands. Castration reduces the level of NGF to a value similar to that in females. The factor is made up of two α, two β, and two γ subunits. The β subunits, each of which has a molecular mass of 13,200 Da, have all the nerve growth promoting activity, the α subunits have trypsin-like activity, and the γ subunits are serine proteases. The function of the proteases is unknown. The structure of the β subunit of NGF resembles that of insulin.
NGF is picked up by neurons and is transported in retrograde fashion from the endings of the neurons to their cell bodies. It is also present in the brain and appears to be responsible for the growth and maintenance of cholinergic neurons in the basal forebrain and the striatum. Injection of antiserum against NGF in newborn animals leads to almost total destruction of the sympathetic ganglia; it thus produces an immunosympathectomy. There is evidence that the NGF mediated survival of neurons is actually due to suppression of apoptosis rather than promotion of cell metabolism.
In addition to NGF, there are several other neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and NT-4/5. They each maintain a different pattern of neurons, although there is some overlap. NT-3 is important for proprioceptor neurons that innervate the muscle spindle and mechanoreceptors in the skin; NT-4/5 is important for neurons that innervate the hair follicle; NGF is important for skin nociceptive neurons. Sympathetic neurons depend on both NGF and NT-3. BDNF acts rapidly and can actually depolarize neurons. BDNF-deficient mice lose peripheral sensory neurons and have severe degenerative changes in their vestibular ganglia and blunted long-term potentiation.
These four established neurotrophins and their three high affinity tyrosine kinase associated (Trk) receptors are listed in Table 1. Each of these Trk receptors dimerizes, and this initiates phosphorylation in the cytoplasmic tyrosine kinase domains of the receptors. An additional low-affinity NGF receptor that is a 75-kDa protein is called the p75 receptor. This receptor binds all four of the listed neurotrophins with equal affinity. Interestingly, if a p75 receptor becomes activated in the absence of exposure to a neurotrophin, it causes apoptosis or cell death, an effect opposite to the usual growth promoting and nurturing effects of neurotrophins. Research is ongoing to characterize the distinct roles of p75 and Trk receptors and factors that influence their expression in neurons.
Table1. Neurotrophins.
OTHER FACTORS AFFECTING NEURONAL GROWTH
The regulation of neuronal growth is a complex process. Schwann cells and astrocytes produce ciliary neurotrophic fac tor (CNTF). This factor promotes the survival of damaged and embryonic spinal cord neurons and may prove to be of value in treating human diseases in which motor neurons degenerate. Glial cell line–derived neurotrophic factor (GDNF) maintains the survival of midbrain dopaminergic neurons and pre vents the apoptosis of spinal motor neurons. Another factor that enhances the growth of neurons is leukemia inhibitory factor (LIF). In addition, neurons as well as other cells respond to insulin-like growth factor I (IGF-I) and the various forms of transforming growth factor (TGF), fibroblast growth fac tor (FGF), and platelet-derived growth factor (PDGF).
Clinical Box 1 compares the ability to regenerate neurons after central and peripheral nerve injury.
CLINICAL BOX-1
