You are investigating how the number of nerve cells is regulated in a specific t

Question

You are investigating how the number of nerve cells is regulated in a specific tissue of your favorite experimental organism. You isolate a mutant that contains almost none of these nerve cells in the adult animal, and you hypothesize that in this mutant the nerve cells are either not made or do not connect to their target cells and therefore fail to get the survival signals they need. You are surprised by the results of a developmental time course that you perform. You find that in the mutant more of the nerve cells are made than in controls, and they all connect correctly to their target cells. But then, at later times, nearly all of the nerve cells undergo apoptosis. What could be the explanation?

Explanation / Answer

Nervous tissue is the main component of the nervous system - the brain, spinal cord, and nerves-which regulates and controls body functions. It is composed of neurons, which transmit impulses, and the neuroglia cells, which assist propagation of the nerve impulse as well as provide nutrients to the neuron. Nervous tissue is made of nerve cells that come in many varieties, all of which are distinctly characteristic by the axon's or long stem like part of the cell that sends action potential signals to the next cell. Functions of the nervous system are sensory input, integration, control of muscles and glands, homeostasis, and mental activity. For proliferative tissues to maintain a constant size and function properly, the older cells must die to make way for new cells. Such ‘programmed’ death involves a stereotyped sequence of biochemical and morphological changes that allows the cell to die without adversely affecting its neighbours — a process called apoptosis (FIG. 1). In many diseases, aberrant regulation of apoptosis is the central abnormality. For example, resistance of cells to apoptosis is thought to be responsible for many types of cancer, and identification of the molecular alterations responsible for such cell immortalization is an important area in cancer research 1 . Although details of the definition of apoptosis vary among investigators, there is general agreement that apoptosis is a cell death process involving caspase activation and a lack of cell swelling with maintenance of organelle (mitochondria and endoplasmic reticulum) integrity. Apoptosis occurs within a tissue in a ‘spotty’ pattern such that healthy and dying cells are intermingled. This contrasts with another form of cell death, called necrosis, in which cellular organelles swell and the plasma membrane lyses, resulting in massive death of groups of cells throughout a tissue.As described below, the criteria for apoptosis are fulfilled in many neurological disorders in which neuronal death is a central feature. In contrast to the rapid turnover of cells in proliferative tissues, neurons commonly survive for the entire lifetime of the organism — this enduring nature of neurons is necessary for maintaining the function of those cells within neuronal circuits. For example, motor neurons must maintain connections to skeletal muscles, and long-term memories probably require the continued survival of the neurons in the regions of the brain in which those memories are encoded. During development of the central and peripheral nervous systems, many neurons undergo apoptosis during a time window that coincides with the process of SYNAPTOGENESIS 2 . Signals that determine whether or not developing neurons live or die may include competition for a limited supply of target-derived NEUROTROPHIC FACTORS and activation of receptors for the excitatory neurotransmitter glutamate 3 . Initial overproduction of neurons, followed by death of some, is probably an adaptive process that provides enough neurons to form nerve cell circuits that are precisely matched to their functional specifications 4 . Accordingly, the decision as to which neurons die is made by cellular signal transduction pathways that are ‘tuned’ to the functionality of neuronal circuits. Unfortunately, many people experience excessive death of one or more populations of neurons as the result of disease or injury. For example, death of hippocampal and cortical neurons is responsible for the symptoms of Alzheimer’s disease; death of midbrain neurons that use the neurotransmitter dopamine underlies Parkinson’s disease; Huntington’s disease involves the death of neurons in the striatum, which control body movements; and death of lower motor neurons manifests as amyotrophic lateral sclerosis (FIG. 2). The number of people with such neurodegenerative disorders is rapidly increasing as the average lifespan gets longer. Neuronal death cascades Many signals can initiate or ‘trigger’ apoptosis in neurons (FIG. 3). The best-studied signal is lack of neurotrophic factor support, which may trigger apoptosis during development of the nervous system and possibly in neurodegenerative disorders 2–4 . Most neurons in the mammalian central nervous system possess receptors for another trigger of apoptosis — the excitatory neurotransmitter glutamate. Overactivation of glutamate receptors can induce apoptosis by a mechanism involving calcium influx 5,6 , and such ‘excitotoxicity’ may occur in acute neurodegenerative conditions such as stroke, trauma and severe epileptic seizures, as well as in Alzheimer’s disease and motor system disorders 7,8 . A third trigger of neuronal death is increased oxidative stress, in which free radicals (such as the superoxide anion radical and the hydroxyl radical) damage cellular lipids, proteins and nucleic acids by attacking chemical bonds in those molecules 9,10 .METABOLIC STRESS, as occurs after a stroke or during ageing, may also initiate neuronal apoptosis. Finally, environmental toxins can induce neuronal apoptosis, and several such toxins can induce patterns of brain damage and behavioural phenotypes remarkably similar to Parkinson’s and Huntington’s diseases 11

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