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Survival of Certain Neurons Depends on NGF

Figure 9.28 Nerve growth factor was purified on the basis of its ability to induce neurite outgrowth. In addition, NGF was shown to be required for the survival of sympathetic neurons. These early studies suggested that a supply of an endogenous factor is limiting for the survival and growth of dependent cell populations.

Early studies on cultured sensory and sympathetic neurons suggested that they require a target-derived factor (nerve growth factor, NGF) for their survival. Competition for NGF occurs when multiple axons innervate a single target that has limited amounts of NGF. Innervating axons possess NGF receptors that bind, internalize, and retrogradely transport NGF. The biochemical cascade produced by NGF internalization and transport results in signals that prevent cell death.

The prototypic trophic factor is NGF; purified NGF is a complex of three protein subunits (alpha, beta, gamma):

alpha: this subunit has an unknown function
beta: this component has biological activity (dimer)
gamma: this subunit has proteolytic activity

One of the first physiological roles that was discovered for NGF was its importance in the survival of sensory and sympathetic neurons. If anti-NGF antibodies are injected into newborn animals to "neutralize" the actions of NGF the survival of sympathetic neurons is greatly reduced.

 

Figure 9.29 Nerve growth factor is a retrograde survival factor. NGF (red dots) is bound by receptors on the blue cell and is retrogradely transported down its axon to the cell body where it affects cell growth, differentiation, and transcription of other genes.		Figure 9.30 NGF is secreted by target cells and bound by receptors on the dependent cell. After binding, the receptor/ligand complex is internalized in a vesicle within the axon terminal. These endocytic vesicles are transported on microtubules to the cell body where NGF disassociates from its receptor and can affect transcriptional machinery and cellular differentiation.

 

Figure 9.31 The cellular actions of growth factors (NGF, BDNF, NT-3, NT-4) are mediated by specific cell surface receptors. See the text below for more information.

For developing neurons in the superior cervical ganglion the natural source of NGF can be blocked by the daily injections of anti-NGF antibodies into newborn animals. This treatment results in the premature death of these neurons. In contrast, if newborn animals are injected with NGF itself, the added NGF actually prevents the naturally occurring death of certain types of neurons.

The cellular actions of growth factors (NGF, BDNF, NT-3, NT-4) are mediated by specific cell surface receptors. The high affinity NGF receptor is a tyrosine kinase that confers the biological activity of NGF to cells by acting through downstream signalling processes that eventually involve alterations in gene transcription. This kinase is known as trkA. Other growth factors bind to different receptor tyrosine kinases. For example, TrkB is specifically activated by low concentrations of BDNF and NT-4/5, and can be activated by high concentrations of NT-3.TrkC is related to trkA, but is most effectively activated by NT-3; all trks are transmembrane proteins that contain an extracellular ligand binding domain and an intracellular (cytosolic) tyrosine kinase domain. When trks are activated by the appropriate ligand (e.g., NGF or BDNF) they initiate a series of intracellular signaling cascades.

 

 

 

 

 

 

 

Figure 9.32 Possible consequences of NGF deprivation in cells. Withdrawal of NGF from dependent cells results in the initiation of signalling processes that eventually result in cell death. Specific cellular events are in black along a continuum from signalling processes to DNA cleavage. Possible targets for therapeutic intervention are in red.

 

Figure 9.33 Sources of trophic support for motor neurons of the spinal cord. Motor neurons (purple/blue) receive trophic support from a number of sources. Axon terminals receive diffusable (1) or matrix-associated (2) factors from muscle. Schwann cells (3) and glial cells (4) including astrocytes and oligodendrocytes can also provide trophic support. Afferents from the DRG (5) and autocrine (6), paracrine (6), or circulating factors can also influence motor neuron survival.

NGF is related to other trophic factors such as BDNF, NT-3, NT-4, and CNTF. These factors are structurally related to NGF and are survival factors for neurons that do not respond to NGF. Trophic signals produced by some of these molecules are not all target-derived like NGF. Neurons may receive trophic signals from molecules in the extracellular matrix, from glia, and in an autocrine or paracrine manner. Withdrawal of these factors results in cell death for neuronal populations that are dependent on these factors.

Disruption of different neurotrophin genes in mice has allowed analysis of the role of these factors in sensory-motor pathways. The dorsal root ganglia (DRG) of wild-type mice possess small (red), medium (green), and large (blue) cells. The small cells that carry pain and temperature information are lost when NGF or its high affinity receptor, trkA, are missing. Large cells that innervate muscle spindles are lost when NT-3 or TrkC are missing. These data underline the importance of different neurotrophins in supporting the development of distinct cell populations.

Figure 9.34