Development and the Molecular Biology of Eukaryotes Help (page 2)
The term ontogeny represents the development of an individual from zygote to maturity; embryology is the study of early ontogenic events. Epigenesis is the modern concept that development of differentiated cells, tissues, and organs occurs by cells acquiring new structures and functions while increasing in size and complexity. The relatively new field of evolutionary developmental biology (also called evo-devo) compares developmental processes among different species to gather information regarding how developmental pathways evolved and contribute to our understanding of the relatedness of various species.
Determination and Differentiation
After fertilization, the new diploid nucleus exists in a primarily maternal cytoplasm. This environment is critical for proper development of the embryo. There are mRNAs and proteins present, supplied by the maternal cytoplasm, that help guide the developing zygote. These mRNAs and proteins are encoded by maternal effect genes because mutations in these genes only have an effect if they originate in the mother. The nucleus begins to divide and zygotic genes are expressed. This further establishes local environments that are important for development. Ultimately, the cell number of the embryo begins to increase, and groups of cells are determined to become a particular organ or tissue (e.g., muscle cells that contract, neurons that transmit impulses, fibroblast cells that manufacture extracellular collagen or elastic fibers). This process is called cell fate determination. As subsequent gene expression programs ensue, fated cells become differentiated into their final functional state. Thus, development involves the differentiation of cells into specific types and tissues.
One of the primary mechanisms governing the developmental process is transcriptional control. It is thought that relatively few master control switches exist, and that they are arranged in a hierarchy, with early-acting genes controlling the expression of other genes that act at later times in development. The products of these master control genes that determine specific developmental pathways are called morphogens. Morphogens exert their effects through a gradient of their concentration. Induction is the determination of the developmental fate of one cell mass by another. This morphogenetic effect is brought about by a living part of an embryo (called an inducer or organizer) acting upon another part (competent tissue) via one or more morphogens. An undifferentiated cell may, under the influence of a mutant master control gene, follow a developmental pathway different from that which it normally would pursue (transdetermination), usually with bizarre (if not lethal) consequences.
Much of our understanding of development has come from studies of the fruit fly Drosophila. Many aspects of development are similar for eukaryotes in general (i.e., epigenesis, determination, and differentiation); however, some aspects are not shared. For example, maternal effect mutations have not been isolated in some genetic model systems (e.g., Arabidopsis) and development in C. elegans is highly dependent on cell-cell contact and communication, as opposed to gradients of morphogens.
EXAMPLE 13.17 In the fruit fly Drosophila, the genes that control development of its body plan can be grouped into three classes. Maternal effect genes are those genes of the mother that establish the organization of the egg through gradients of concentration. The embryo contains segmentation genes that establish the segmentation pattern of the fly. The embryo's homeotic genes switch on after the segmentation genes and establish the kind of structure that will develop in each body segment. Mutations in homeotic genes can cause a normal body part to develop in an abnormal location, e.g., a leglike antenna in Drosophila. A common conserved DNA sequence of about 180 bp (called a homeobox) is shared in most of the known homeotic genes and with at least some of the segmentation genes. The homeobox motif is usually repeated several times in one gene and gives rise to a 60 amino acid domain called a homeodomain. Homeodomains are very basic and have a helix-turn-helix motif that characterizes several well-known DNA binding proteins (e.g., CAP and lambda phage repressor). Homeotic genes act as transcriptional regulators that are thought to form a network of master control genes that switch on batteries of other genes whose activities specify the kind of body structure that will develop. Similar homeoboxes have been found in other invertebrates as well as in some vertebrates, including mammals, in which they are called Hox genes. But at present it is not known if they function in the same way as in Drosophila.
Maternal effect genes may provide certain substances or organize the egg cytoplasm in such a way that development of certain progeny phenotypes is essentially totally controlled by the maternal genotype rather than by the genotype of the embryo. Such effects may be ephemeral or may persist throughout the life of an individual. The substances that produce maternal effects are not self-perpetuating, and therefore must be synthesized anew for each generation of progeny by the appropriate maternal genotype.
EXAMPLE 13.18 A dominant gene K in the meal moth Ephestia produces a hormone-like substance called kynurenine that is involved in pigment synthesis. The recessive genotype kk is devoid of kynurenine and cannot synthesize pigment. Females of genotype Kk can produce k-bearing eggs containing a small amount of kynurenine. For a short time during early development, a larva may use this supply of kynurenine to develop pigment even though its own genotype might be kk. The color fades as the larva grows older because the maternally supplied kynurenine becomes depleted.
EXAMPLE 13.19 The direction in which the shell coils in the snail Limnaea can be dextral like a right-hand screw or sinistral like a left-hand screw. The maternal genotype organizes the cytoplasm of the egg in such a way that cleavage of the zygote will follow either of these two patterns regardless of the genotype of the zygote. If the mother has the dominant gene s+, all her progeny will coil dextrally; if she is of the genotype ss, all her progeny will coil sinistrally. This coiling pattern persists for the life of the individual. See Solved Problem 13.2.
EXAMPLE 13.20 There are three important maternal effect genes in the fruit fly: bicoid, hunchback, and nanos. The bicoid and hunchback proteins are localized to the anterior portion of the egg and establish an anterior polarity in the egg. Bicoid is a transcription factor that activates the expression of hunchback. Hunchback, in turn, is a transcription factor that activates the transcription of other genes that are involved in the formation of head and thorax structures. Hunchback also represses the production of genes involved in posterior structures. The nanos protein is localized in the posterior of the egg. It acts as a translational repressor of hunchback mRNA. This suppresses the development of anterior features in the posterior of the egg and allows for expression of posterior feature regulators.
Depending on the signals it receives, the cell type and the species, a differentiated cell may or may not be able to dedifferentiate (revert to an unspecialized state). Differentiation is usually reversible at the nuclear level, as evidenced from nuclear transplantation experiments. However, fully differentiated cells often are incapable of replication. For example, spinal nerve cells, mature red blood cells (erythrocytes) and plasma cells can no longer divide. The undifferentiated stem cells from which mature blood cells are derived retain the capacity to replicate and differentiate into various blood cell types. Differentiation is seldom due to gain or loss of chromosomes or of genetic material (lymphocytes are a notable exception).
EXAMPLE 13.21 Antibodies are made by white blood cells (lymphocytes) known as plasma cells. Lymphoid stem cells in the bone marrow differentiate into B cells that can complete their maturation into antibody-secreting plasma cells after making specific contact with an antigen via their membrane receptor (an antibody molecule). An immunoglobulin (antibody) molecule is a tetramer composed of two identical heavy (H) polypeptide chains and two identical light (L) chains. There are five classes of immunoglobulin molecules (IgG, IgM, IgA, IgE, and IgD) based upon the structure of their heavy chains (γ; μ; α; ε, and δ, respectively). There are only two types of L chains (κ and λ). The carboxy ends of heavy and light chains possess amino acid sequences (called constant regions, designated ''C'') that are invariate within each H chain class and L chain type. The free amino ends of each chain differ in amino acid sequence and are referred to as variable (''V'') regions. The V regions of an L chain and an H chain together form an antigen-binding site. The CH region consists of three or four similar segments, presumably evolved by duplication of an ancestral gene, followed by subsequent mutational modifications; these similar segments are called ''domains'' and are labeled CH1, CH2, CH3.
A mature plasma cell produces antibodies bearing a single class of H chain and a single class of L chain, hence also a single antigen-binding specificity. Although an individual may inherit different genes for the H and L chains, an unknown mechanism allows expression of only one gene for each of these chains, a phenomenon known as allelic exclusion. The first antibodies produced by a plasma cell are usually of class IgM. Later in that same cell, the same antigen-binding specificity may be associated with H chains of a different class (e.g., IgG or IgA). At any given time, however, a plasma cell is thought to synthesize primary mRNA H-chain transcripts of a single kind.
There are three immunoglobulin gene families: two for the light chain types (κ and λ) and one for the heavy chains, each on a different human autosome. Within each gene family, there usually are multiple DNA sequences (sometimes hundreds) coding for the V region of an immunoglobulin chain. There are also one or more sequences coding for the C region of that same chain. In embryonic lymphoid cells, the V and C segments of a gene family that ultimately code for a given immunoglobulin chain are not adjacent to one another, but are only loosely linked. As the cell matures into an antibody-secreting plasma cell, the V and C sequences become more tightly linked. The V and C sequences are ''exons'' that code for portions of the immunoglobulin polypeptide chain. An apparently random choice is made to connect one of the Vexons to one of the C exons, and all unnecessary intervening material (exons or introns) is deleted (sometimes at the DNA level). Between the V and C regions there are a few J (for ''joining'') exons in both L- and H-chain families; the H-chain family also contains a few additional D (for ''diversity'') exons. These J and D segments contribute to hypervariable regions (also known as complementarity-determining regions, CDRs) that form part of an antigen-binding cavity in an immunoglobulin molecule. A light-chain Vexon is joined to a J exon by a single recombination event. The V-J complex is then connected to a C exon at the level of mRNA by the standard RNA-splicing mechanism. Two recombination events are required to assemble a heavy-chain gene. The first event joins the J and D exons; the second event joins the Vexon with the D-J complex to form a V-D-J complex. Since the joining of V-J or V-D-J is imprecise, this produces the phenomenon termed junctional diversity in the possible kinds of immunoglobulin chains. As a heavy-chain gene is being assembled, extra nucleotides (called N regions) can be inserted in a template-free fashion between the V-D or D-J segments. The random association of any Vexon with any J or J-D complex is called combinatorial translocation. AV-D-J complex can be coupled to a C exon by either of two mechanisms. RNA splicing can connect the V-D-J group with one of the nearest C exons (either μ, or δ). Alternatively, the V-D-J group can be connected to more remote C exons (γ; α; or ε) by a third DNA recombination; this latter mechanism is known as class switching. A high level of point mutations in fully assembled antibody genes is another source of diversity called somatic hypermutation. In the formation of a tetrameric immunoglobulin molecule, two identical L chains can be associated with any two identical H chains, an option known as combinatorial association.
Estimates of the number of immunoglobulin components in the mouse are as follows. L chains (κ-type only) have 250 V and 4 J regions, and three sites for junctional diversity; total number of κL chains = 250 × 4 × 3 = 3000. H chains have 250 V, 10 D and 4 J regions, plus three sites for junctional diversity at both V-D and D-J joints; total number of H chains = 250 × 10 × 4 × 3 × 3 = 90; 000. Combinatorial association of 3000 L chains with 90,000 H chains = 2:7 × 108 possible antibody molecules. This is an underestimate because it does not consider lambda L chains, N regions, somatic hypermutation, or the five classes (C exons) of the heavy chains. Moreover, in humans there are four different CH exons for the four subclasses (unrelated to the number of CH domains) of IgG, two each for IgM and IgA, and one each for IgD and IgE; for L chains there are four CL exons for the four subtypes of the lambda family and one in the kappa family. Different CH classes endow the immunoglobulin molecules with special effector functions such as complement binding (IgG and IgM), placental passage (IgG), secretion into body fluids (IgA), and binding to mast cells (IgE). Thus, the union of one kind of variable region with one kind of constant region in H chains contributes to an antibody-combining site that specifically binds antigen and also allows the immunoglobulin molecule to become biologically active.
The phenomenon of programmed cell death is termed apoptosis. Apoptosis is necessary in several developmental processes to eliminate certain cells in an area where more specialized or different cell types will develop. For example, in insect morphogenesis, the cells of the larval stage must die and hydrolyze in order for entirely new cells with new functions to form. Apoptosis involves cell compaction, chromatin condensation, DNA fragmentation, and membrane blebbing. Dying cells ultimately fall apart and are engulfed by surrounding cells.
EXAMPLE 13.22 In the worm, C. elegans, 131 of the 1090 cells die predictably during the development of the mature organism. The programmed cell death of these cells is governed primarily by three genes. The ced-3 and ced-4 genes cause cells to die and the ced-9 gene regulates their expression. Cells expressing ced-9 survive and cells lacking ced-9 die. Thus, ced-9 blocks the expression of ced-3 and ced-4.
The over expression of genes homologous (similar) to ced-9 in humans can lead to cancerous growth. Cancer is basically the dedifferentiation and division of terminally differentiated and normally nondividing cells. Genes whose inappropriate expression leads to cancer are called oncogenes. Inappropriate expression of genes similar to ced-3 and ced-4 can lead to degenerative diseases in which tissue cells are instructed to die early.
Practice problems for these concepts can be found at:
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