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Neurotrophic Factors in Development and Programmed Cell Death

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During animal development, neurons are overproduced, but when contacts with other cells and neurons are formed, the excess of neurons is removed by genetically controlled programmed cell death (PCD). This process ensures correct formation of neuronal contacts and the system match between the neurons and their targets, which are critically important for the development of vertebrate nervous system.1 Experimental data demonstrate that different cell-intrinsic and cell-extrinsic factors regulate this process, including cell-intrinsic transcriptional programs, as well as growth factors secreted in the autocrine manner. Cell-extrinsic factors include secreted or cell-surface-bound molecules provided by the neighboring cells, tissues and extracellular matrix. Neurotrophic factors (NTFs) are important groups of proteins secreted by the target tissues and inhibiting PCD of the neurons innervating these targets. NTFs provide trophic support for the neurons by keeping them alive and maintaining their phenotype.

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During developmental periods of PCD, from 20% to 80% of neurons in a given population die by apoptosis.2 NTFs play a key role in preventing apoptotic death, thereby regulating the number of target-innervating neurons and the density of innervation.

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Mechanisms of Neurotrophic Factors

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The concept of NTFs was formulated by Rita Levi-Montalcini and Victor Hamburger and was based on the studies on nerve growth factor (NGF). It is interesting to note that NGF was the first discovered growth factor and NTF that opened a completely new field in biology.3,4 According to the target-field model,5 neurons are intrinsically apoptotic at PCD and compete for the antiapoptotic NTFs that are secreted by the target tissues in limited amounts. As a result, only those neurons that first reach the target and receive proper neurotrophic support are rescued, whereas those neurons that are late or form synapses with wrong target tissues remain without NTFs and die by default apoptosis (Fig. 7–1). Active killing of the neurons by target-derived NTFs or pro-NTFs has also been postulated as a part of target control upon the number of innervating neurons.6 The NTFs bind to their cognate receptors at neurite terminals, followed by the endocytosis of the ligand-receptor complex. Thereafter, the complex is retrogradely transported along the axon to the cell soma.7 Binding of the ligand triggers the receptor activation, which usually means phosphorylation on tyrosine, serine, or threonine residues in the intracellular part of the transmembrane receptors. Phosphorylated amino acids form docking sites for the adaptor proteins or enzymes that activate downstream survival, promoting signaling pathways, and thereby suppress the apoptotic program. The role of NTF in the development of the peripheral nervous system, (PNS) is well established, but the role of NTFs in the development and maintenance of the central nervous system (CNS) is less clear, although currently actively studied.

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Figure 7–1.
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Target dependence of the neurons during ...

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