CONTROL OF APOPTOTIC PATHWAYS IN DEVELOPMENT
Although controlling the onset of apoptosis is very complex, the ramifications of losing control are dire. Too much apoptosis or inappropriate activation of apoptosis can destroy fully functioning cells. Death of too much tissue can kill a developing organism. Not enough apoptosis, especially during development, can create surplus tissue and disrupt the normal operation of tissues and organisms. Many disease states may arise from inappropriate or defective apoptosis. In C. elegans sex development depends on apoptosis. C. elegans comes in two “sexes,” males, which produce only sperm, and hermaphrodites, which produce both sperm and eggs. No true females are produced. The decision to become male or hermaphrodite hinges on apoptosis ( Fig. 20.19 ). Two neurons control the muscles around the vulva so that eggs can be laid. If the neurons are present, the worm is a hermaphrodite. If the neurons are absent, the worm cannot lay eggs, essentially making it a male. The presence or absence of these hermaphrodite-specific neurons (HSN) depends on apoptosis. Defects in ced-3 or elg-1 affect whether the worm is male or hermaphrodite. Without elg-1 , too much apoptosis occurs; therefore, all worms are missing the HSN and no egg-laying worms are produced. Conversely, without ced-3 , apoptosis cannot occur and the HSN survive in all worms.
Apoptosis is tightly regulated during an immune response. During infection, the body responds to the attack by increasing the number of white cells of the immune system. When the infection is past, the body eliminates the surplus immune cells via apoptosis. Immune cells use the death receptor pathway to trigger apoptosis (see earlier discussion). Too much apoptosis would deplete our immune system of essential cells and disable the immune response. During HIV infection, the number of T-cells plummets to dangerously low levels, leaving the patient open to many secondary infections. One theory is that HIV kills T cells by inducing apoptosis.
The nervous system is another tissue that is highly sensitive to apoptosis. During development a large number of neuronsundergo apoptosis. One theory suggests that neurons die if they do not receive a “keep on living” signal or trophic factor . If a developing neuron reaches its correct destination, it will receive the trophic factor. If the neuron fails to reach its target it gets no trophic factor and enters apoptosis by default. If neurons are cultured in a laboratory dish, removal of one trophic factor, nerve growth factor , induces the cells to undergo apoptosis ( Fig. 20.20 ). Addition of caspase inhibitors blocks cell death, proving the cells were dying via apoptosis. During mouse development, embryos with defective genes for either caspase-3 or caspase-9 die. Lack of apoptosis in the developing neural system is the main cause for death in both cases. In the adult brain, apoptosis of neurons causes irreparable damage because neurons do not regenerate. Extensive apoptosis may play a role in manydiseases, such as Alzheimer’s (see later discussion), Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). The exact role of apoptosis in these diseases is still being investigated.
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