C Neuron Survival Factors

The survival of axotomized neurons is promoted by neurotrophic factors, neurotransmitters, and neuropep-

tides, and their receptors (table 5.1). These factors are made primarily by dedifferentiated Schwann cells (Fu and Gordon, 1997; Yannas, 2001). Reduction or denial of access to these factors results in neuronal cell death. The sensory neurons of the dorsal root ganglion are particularly sensitive to lack of survival factors, whereas motor neurons survive for periods of more than one year (Fu and Gordon, 1997).

The neurotrophins are an important family of molecules secreted by Schwann cells that are essential for the survival of axotomized neurons. This family includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT-3, NT-4). NGF supports the survival of sensory and sympathetic axons, whereas BDNF, NT-3, and NT-4 promote survival of regenerating motor neurons (Raivich and Kreutzberg, 1993; Birling and Price, 1995; Fu and Gordon, 1997). The neurotrophins act through specific receptor tyrosine kinases (Trks). NGF acts through TrkA, BDNF and NT-4 through TrkB, and NT-3 through TrkC. In addition, all the neurotrophins bind to a common low-affinity receptor, p75NTR, which selectively modulates the Trk-mediated survival response of neurons to the various neurotrophins (Davies, 2000).

Ciliary neurotrophic factor (CNTF) and IL-6, which share common structural motifs and use JAK/STAT signaling pathways, and glial derived neurotrophic factor (GDNF), are also important to the survival of axotomized neurons (Fu and Gordon, 1997). CNTF is released from Schwann cells after injury; macrophages and fibroblasts are the primary producers of IL-6. GDNF enhances survival of axotomized motor neurons and is produced primarily by Schwann cells (Fu and Gordon, 1997).

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