Genes VII

The systematic manner in which the regulators are turned on and off to form circuits that determine body parts has been worked out in D. melanogaster. The basic principle is that a series of events resulting from the initial asymmetry of the egg is translated into the control of gene expression so that specific regions of the egg acquire different properties. The means by which asymmetry is translated into control of gene expression differ for each of four systems that have been characterized in the insect egg. It may involve localization of factors that control transcription or translation within the egg, or localized control of the activities of such factors. But the end result is the same: spatial and temporal regulation of gene expression.

This initial stage of development is succeeded by a stage at which the identities of parts of the embryo are determined: regions are defined whose descendants will form particular body parts. The genes that regulate this process are identified by loci in which mutations cause a body part to be absent, to be duplicated, or to develop as another body part. Such loci are prime candidates for genes whose function is to provide regulatory "switches." Most of these genes code for regulators of transcription. They act upon one another in a hierarchical manner, but they act also upon other genes whose products are actually responsible for the formation of pattern. The ultimate targets are genes that code for kinases, cytoskeletal elements, secreted proteins, and transmembrane receptors.

Viewing the process as a whole, we see that the establishment of differences in the patterns of transcription in different regions of the embryo leads to a cascade of control, when regulatory events are connected so that a gene turned on (or off) at one stage itself controls expression of other genes at the next stage. Formally, such a cascade resembles those described previously for bacteriophages or for bacterial sporulation (as discussed previously in 10 The operon), although it is more complex in the case of eukaryotic development. In this paradigm, the common feature of regulatory proteins is that they are transcription factors that regulate the expression of other transcription factors (as well as other target proteins). As in the case of prokaryotic regulation, the basic relationship between the regulator protein and the target gene is that the regulator recognizes a short sequence in the DNA of the promoter (or an enhancer) of a target gene. All of the targets for a particular regulator are identified by their possession of a copy of the appropriate consensus sequence.

The development of an adult organism from a fertilized egg follows a predetermined pathway, in which specific genes are turned on and off at particular times. From the perspective of mechanism, we have most information about the control of transcription. However, subsequent stages of gene expression are also targets for regulation. And, of course, the cascade of gene regulation is connected to other types of signaling, including cell-cell interactions that define boundaries between groups of cells.

The mechanics of development in terms of cellular events are different in different types of species, but we assume that the principle established with Drosophila will hold in all cases: that a regulatory cascade determines the appropriate pattern of gene expression in cells of the embryo and ultimately of the adult. Indeed, homologous genes in distantly related organisms play related roles in development. The same pathways are found in (for example) flies and mammals, although the consequences of their employment are rather different in terms of the structures that develop.

Genes involved in regulating development are identified by mutations that are lethal early in development or that cause the development of abnormal structures. A mutation that affects the development of a particular body part attracts our attention because a single body part is a complex structure, requiring expression of a particular set of many genes. Single mutations that influence the structure of the entire body part therefore identify potential regulator genes that switch or select between developmental pathways.

In Drosophila, the body part that is analyzed is the segment, the basic unit that can be seen looking at the adult fly. Mutations fall into (at least) three groups, defined by their effect on the segmental structure:

• Maternal genes are expressed during oogenesis by the mother. They may act upon or within the maturing oocyte.
• Segmentation genes are expressed after fertilization. Mutations in these genes alter the number or polarity of segments. Three groups of segmentation genes act sequentially to define increasingly smaller regions of the embryo.
• Homeotic genes control the identity of a segment, but do not affect the number, polarity, or size of segments. Mutations in these genes cause one body part to develop the phenotype of another part.

The genes in each group act successively to define the properties of increasingly more restricted parts of the embryo. The maternal genes define broad regions in the egg; differences in the distribution of maternal gene products control the expression of segmentation genes; and the homeotic genes act on segment identity at around the time that the last group of segmentation genes are defining the segments (for review see Mahowald and Hardy, 1985; Lawrence, 1992).