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Identity of individual segments defined

121.12 A cascade of gene regulation establishes the polarity and identity of individual segments of Drosophila. In development, successively smaller regions of the embryo are determined.

Programmed Cell Death in Development

Cell death is an integral part of multicellular life. Cells in many tissues have a limited life span, and they die and are replaced continually by new cells. Cell death shapes many body parts during development: it is responsible for the disappearance of a tadpole's tail during metamorphosis and causes the removal of tissue between the digits to produce the human hand. Cell death is also used to eliminate dangerous cells that have escaped normal controls (see next section on cancer).

Cell death in animals is often initiated by the cell itself in a kind of cellular suicide termed apoptosis. In this process, a cell's DNA is degraded, its nucleus and cytoplasm shrink, and the cell undergoes phagocytosis by other cells without any leakage of its contents (I Figure 21.13a). Cells that are injured, on the other hand, die in a relatively uncontrolled manner called necrosis. In this process, a cell swells and bursts, spilling its contents over neighboring cells and eliciting an inflammatory response (I Figure 21.13b). Apoptosis is essential to embryogenesis; most multicellular animals cannot complete development if the process is inhibited.

Surprisingly, most cells are programmed to undergo apoptosis and will survive only if the internal death pro gram is continually held in check. The process of apoptosis is highly regulated and depends on numerous signals inside and outside the cell. Geneticists have identified a number of genes having roles in various stages of the regulation of apoptosis. Some of these genes encode enzymes called cas-pases, which cleave other proteins at specific sites (after aspartic acid). Each caspase is synthesized as a large, inactive precursor (a procaspase) that is activated by cleavage, often by another caspase. When one caspase is activated, it cleaves other procaspases that trigger even more caspase activity. The resulting cascade of caspase activity eventually cleaves proteins essential to cell function, such as those supporting the nuclear membrane and cytoskeleton. Caspases also cleave a protein that normally keeps an enzyme that degrades DNA (DNAse) in an inactive form. Cleavage of

(a) Apoptosis

(b) Necrosis

Cell and nucleus shrink; nucleus fragments.

Macrophage

Cell and nucleus shrink; nucleus fragments.

Macrophage

Shrinking continues and cell is engulfed by macrophage.

4 Macrophage phagocytizes apoptotic cell.

Shrinking continues and cell is engulfed by macrophage.

4 Macrophage phagocytizes apoptotic cell.

21.13 Programmed cell death by apoptosis is distinct from uncontrolled cell death through necrosis.

this protein activates DNAse and leads to the breakdown of cellular DNA, which eventually leads to cell death.

Procaspases and other proteins required for cell death are continuously produced by healthy cells, so the potential for cell suicide is always present. A number of different signals can trigger apoptosis; for instance, infection by a virus can activate immune cells to secrete substances onto an infected cell, causing that cell to undergo apoptosis. This process is believed to be a defense mechanism designed to prevent the reproduction and spread of viruses. Similarly, DNA damage can induce apoptosis and thus prevent the replication of mutated sequences. Damage to mitochondria and the accumulation of a misfolded protein in the endo-plasmic reticulum also stimulate programmed cell death.

Apoptosis in animal development is still poorly understood but is believed to be controlled through cell-cell signaling. The cell death that causes the disappearance of a tadpole's tail, for example, is triggered by thyroxin, a hormone produced by the thyroid gland that increases in concentration during metamorphosis. The elimination of cells between developing fingers in humans is thought to result from localized signals from nearby cells.

The symptoms of many diseases and disorders are caused by apoptosis or, in some cases, its absence. In neu-rodegenerative diseases such as Parkinson disease and Alzheimer disease, symptoms are caused by a loss of neurons through apoptosis. In heart attacks and stroke, some cells die through necrosis, but many others undergo apoptosis. Cancer is often stimulated by mutations in genes that regulate apoptosis, leading to a failure of apoptosis that would normally eliminate cancer cells.

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Cells are capable of apoptosis (programmed cel death), a highly regulated process that depends on enzymes called caspases. Apoptosis plays an important role in animal development and is implicated in a number of diseases.

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apoptosis

Additional information on

Evo-Devo: The Study of Evolution and Development

"Ontogeny recapitulates phylogeny" is a familiar phrase that was coined in the 1860s by German zoologist Ernst Haeckel to describe his belief—now considered wrong—that organisms repeat their evolutionary history during development. According to Haeckel's theory, a human embryo passes through fish, amphibian, reptilian, and mammalian stages before developing human traits.

Although ontogeny does not recapitulate phylogeny, many evolutionary biologists today are turning to the study of development for a better understanding of the processes and patterns of evolution. Sometimes called "evo-devo," the study of evolution through the analysis of development is revealing that the same genes often shape developmental pathways in distantly related organisms. In humans and insects, for example, the same gene controls the development of eyes, despite the fact that insect and mammalian eyes are thought to have evolved independently. Similarly, biologists once thought that segmentation in vertebrates and invertebrates was only superficially similar, but we now know that, in both Drosophila and amphioxus (a marine organism closely related to vertebrates), a gene called engrailed divides the embryo into specific segments. A gene called distalless, which creates the legs of a fruit fly, has also been found to also play a role in the development of crustacean branched appendages. This same gene also stimulates body outgrowths of many other organisms, from polycheate worms to starfish.

Similar genes may be part of a developmental pathway common to two different species but have quite different effects. For example, a Hox gene called AbdB helps define the posterior end of a Drosophila embryo; a similar group of genes in birds divides the wing into three segments. In another example, the sog gene in fruit flies stimulates cells to assume a ventral orientation in the embryo, but the expression of a similar gene called chordin in vertebrates causes cells to assume dorsal orientation, exactly the opposite of the situation in fruit flies.

The theme emerging from these studies is that a small, common set of genes may underlie many basic developmental processes in many different organisms. Although Haeckel's euphonious phrase "ontogeny recapitulates phy-logeny" was incorrect, evo-devo is proving that development can reveal much about the process of evolution.

Immunogenetics

A basic assumption of developmental biology is that every somatic cell carries an identical set of genetic information and that no genes are lost during development. Although this assumption holds for most cells, there are some important exceptions, one of which concerns genes that encode immune function in vertebrates.

The immune system provides protection against infection by specific bacteria, viruses, fungi, and parasites. The focus of an immune response is an antigen, defined as any molecule that elicits an immune reaction. Although any molecule can be an antigen, most are proteins. The immune system is remarkable in its ability to recognize an almost unlimited number of potential antigens.

The body is full of proteins, so it is essential that the immune system be able to distinguish between self-antigens and foreign antigens. Occasionally, the ability to make this distinction breaks down, and the body produces an immune reaction to its own antigens, resulting in an autoimmune disease (Table 21.5).

The Organization of the Immune System

The immune system contains a number of different components and uses several mechanisms to provide protection against pathogens, but most immune responses can be grouped into two major classes: humoral immunity and cellular immunity. Although it is convenient to think of these classes as separate systems, they interact and influence each other significantly.

Humoral immunity centers on the production of antibodies by special lymphocytes called B cells (I Figure21.14), which mature in the bone marrow. Antibodies are proteins that circulate in the blood and other body fluids, binding to specific antigens and marking them for destruction by phagocytic cells. Antibodies also activate a set of proteins called complement that help to lyse cells and attract macrophages.

Cellular immunity is conferred by T cells (see Figure 21.14), which are specialized lymphocytes that mature in the thymus and respond only to antigens found on the surfaces of the body's own cells. After a pathogen such as a virus has infected a host cell, some viral antigens appear on the cell surface. Proteins, called T-cell receptors, on the surfaces of T cells bind to these antigens and mark the infected cell for destruction. T-cell receptors must simultaneously bind a foreign antigen and a self-antigen called a major histocompatibility complex (MHC) antigen on the cell surface. Not all T cells attack cells having foreign antigens; some help regulate immune responses, providing communication among different components of the immune system.

How can the immune system recognize an almost unlimited number of foreign antigens? Remarkably, each mature lymphocyte is genetically programmed to attack

Table 21.5 Examples of autoimmune diseases

Disease

Tissues Attacked

Graves disease,

Thyroid gland

Hashimoto thyroiditis

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