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Cell Death and Its Regulation

Programmed cell death is a cell fate, an odd sort of cell fate but nonetheless one that is essential. Cell death keeps our hands from being webbed, our embryonic tails from persisting, our immune system from responding to our own proteins, and our brain from being filled with useless electrical connections. In fact, the majority of cells generated during brain development die during development.

Programmed Cell Death Occurs Through Apoptosis

The demise of cells by programmed cell death is marked by a well-defined sequence of morphological changes, collectively referred to as apoptosis, a Greek word that means "dropping off" or "falling off," as leaves from a tree. Dying cells shrink and condense and then fragment, releasing small membrane-bound apoptotic bodies, which generally are engulfed by other cells (Figure 22-26; see also Figure 1-19). The nuclei condense and the DNA is fragmented. Importantly, the in-tracellular constituents are not released into the extracellular milieu where they might have deleterious effects on neighboring cells. The highly stereotyped changes accompanying apoptosis suggested to early workers that this type of cell death was under the control of a strict program. This program is critical during both embryonic and adult life to maintain normal cell number and composition.

The genes involved in controlling cell death encode proteins with three distinct functions:

■ "Killer" proteins are required for a cell to begin the apoptotic process.

■ "Destruction" proteins do things like digest DNA in a dying cell.

■ "Engulfment" proteins are required for phagocytosis of the dying cell by another cell.

At first glance, engulfment seems to be simply an after-death cleanup process, but some evidence suggests that it is part of the final death decision. For example, mutations in killer genes always prevent cells from initiating apoptosis, whereas mutations that block engulfment sometimes allow cells to survive that would normally die. That is, cells with engulfment-gene mutations can initiate apoptosis but then sometimes recover.

In contrast to apoptosis, cells that die in response to tissue damage exhibit very different morphological changes, referred to as necrosis. Typically, cells that undergo this process swell and burst, releasing their intracellular contents, which can damage surrounding cells and frequently cause inflammation.

► FIGURE 22-26 Ultrastructural features of cell death by apoptosis.

(a) Schematic drawings illustrating the progression of morphologic changes observed in apoptotic cells. Early in apoptosis, dense chromosome condensation occurs along the nuclear periphery. The cell body also shrinks, although most organelles remain intact. Later both the nucleus and cytoplasm fragment, forming apoptotic bodies, which are phagocytosed by surrounding cells.

(b) Photomicrographs comparing a normal cell (top ) and apoptotic cell (bottom). Clearly visible in the latter are dense spheres of compacted chromatin as the nucleus begins to fragment. [Part (a) adapted from J. Kuby, 1997, Immunology, 3d ed., W. H. Freeman & Co., p. 53. Part (b) from M. J. Arends and A. H. Wyllie, 1991, Int'l. Rev. Exp. Pathol. 32:223.]

Mild convolution Chromatin compaction and margination Condensation of cytoplasm

Breakup of nuclear envelope Nuclear fragmentation Blebbing

Cell fragmentation

Phagocytosis

Apoptotic body

Phagocytic cell

Mild convolution Chromatin compaction and margination Condensation of cytoplasm

Breakup of nuclear envelope Nuclear fragmentation Blebbing

Cell fragmentation

Neurotrophins Promote Survival of Neurons

The earliest studies demonstrating the importance of trophic factors in cellular development came from analyses of the developing nervous system. When neurons grow to make connections to other neurons or to muscles, sometimes over considerable distances, more cells grow than will eventually survive. Those that make connections prevail and survive; those that fail to connect die.

In the early 1900s the number of neurons innervating the periphery was shown to depend upon the size of the tissue to which they would connect, the so-called "target field." For instance, removal of limb buds from the developing chick embryo leads to a reduction in the number of sensory neurons and motoneurons innervating the bud (Figure 22-27). Conversely, grafting additional limb tissue to a limb bud leads to an increase in the number of neurons in corresponding regions of the spinal cord and sensory ganglia. Indeed, in cremental increases in the target-field size are accompanied by commensurate incremental increases in the number of neurons innervating the target field. This relation was found to result from the selective survival of neurons rather than changes in their differentiation or proliferation. The observation that many sensory and motor neurons die after reaching their peripheral target field suggested that these neurons compete for survival factors produced by the target tissue.

Subsequent to these early observations, scientists discovered that transplantation of a mouse sarcoma tumor into a chick led to a marked increase in the numbers of certain types of neurons. This finding implicated the tumor as a rich source of the presumed trophic factor. To isolate and purify this factor, known simply as nerve growth factor (NGF), scientists used an in vitro assay in which outgrowth of neurites from sensory ganglia (nerves) was measured. Neurites are extensions of the cell cytoplasm that can grow to become the long wires of the nervous system, the axons and dendrites

(a) Amputation of developing limb bud

(b) Transplantation of extra limb bud

Chick embryo

Limb bud

(a) Amputation of developing limb bud

Limb bud

Optic cup and lens

Heart

Spinal cord

Optic cup and lens

Heart

Spinal cord

(b) Transplantation of extra limb bud

Norm hissing limb

Spinal cord (cross section)

Motor neuron generation:

Motor neurons

Motor neurons

Extra limb

Extra limb

^ Motor-neuron apoptosis ^

Motor neuron survival:

▲ EXPERIMENTAL FIGURE 22-27 The survival of motor neurons depends on the size of the muscle target field they innervate. (a) Removal of a limb bud from one side of a chick embryo at about 2.5 days results in a marked decrease in the number of motor neurons on the affected side. In an amputated embryo, normal numbers of motor neurons are generated on both sides (middle). Later in development, many fewer motor neurons remain on the side of the spinal cord with the missing limb than on the normal side (bottom). Note that only about 50 percent of the motor neurons that originally are generated normally survive. (b) Transplantation of an extra limb bud into an early chick embryo produces the opposite effect, more motor neurons on the side with additional target tissue than on the normal side. [Adapted from D. Purves, 1988, Body and Brain: A Trophic Theory of Neural Connections (Cambridge, MA: Harvard University Press), and E. R. Kandel, J. H. Schwartz, and T. M. Jessell, 2OOO, Principles of Neural Science, 4th ed. (New York: McGraw-Hill), p. 1054, Figure 53-11.]

(see Figure 7-29). The later discovery that the submaxillary gland in the mouse also produces large quantities of NGF enabled biochemists to purify it to homogeneity and to sequence it. A homodimer of two 118-residue polypeptides, NGF belongs to a family of structurally and functionally related trophic factors collectively referred to as neurotrophins. Brain-derived neurotrophic factor (BDNF) and neurotro-phin-3 (NT-3) also are members of this protein family.

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