Target Dependent Cell Death and the Discovery of Trophic Factors

The studies of Hamburger and Levi-Montalcini on the role of targets in neural development began with the observation that reduction of a peripheral field (limb) resulted in a size reduction of the innervating primary nerve center. Hamburger and Levi-Montalcini studied the mechanisms by which such changes were brought about.17 They reported on the effect of reduction and augmentation of target size on the development of the spinal ganglia of the chick, examining the rate of proliferation, differentiation, and degeneration. The occurrence of cell degeneration in the spinal ganglia during normal development was noted, and it was observed that there was a distinct topographic pattern of dying cells within the spinal ganglia. It occurred (in normal embryos) most extensively in the cervical and thoracic regions, and was minimal in the brachial and lumbosacral segments. However, limb bud removal caused an extensive cell degeneration within the brachial ganglia (wing bud) or lumbosacral ganglia (hind limb bud). Hamburger proposed that the mechanisms behind cell death in normal and experimental (limb bud extirpation) embryos were the same, and that the enlarged target offered by the developing limb (wing or hind limb) prevented the cell degeneration in the corresponding sensory spinal ganglia. A stated hypothesis was that either synaptic contact with the target or a trophic substance produced in the target area was necessary for cell survival, and that competition for these trophic interactions was what determined whether or not a cell survived or died.

Following these seminal observations, cell death has been noted in many different neuronal populations, and may be a universal developmental phenomenon. Examples include the spinal ganglia and motoneurons, the cranial nerve nuclei, the optic tectum, the retina, and the cerebellum (see Table 1, Reference 18). The phenomenon of cell death is not limited to neurons, but occurs in glial cells as well. About 50% of newly formed oligodendrocytes normally die in the developing rat optic nerve.19 Using cultured O-2A progenitors and oligodendrocytes, Barres showed that cell death can be prevented by the addition of certain growth factors (PDGFs or IGFs), suggesting that survival of cells that effectively compete for factors that are available in limiting quantity is a feature not limited just to neurons.19 Overproduction of oligodendrocytes followed by cell death may be the mechanism behind matching the number of oligos required to myelinate the axons within the optic nerve. It may also allow for even spacing of oligodendrocytes along the length of the axon.19 Peripheral glia, Schwann cells, also undergo programmed cell death during normal development.20 The rate of Schwann cell death appears to be regulated by axon-derived trophic support. In one study aimed at identifying the phenotype of dying cells in developing (postnatal) murine cortex, up 50% of the pyknotic cells were thought to be glia as they were GFAP positive.21

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