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Modern Genetic Analysis Chapter 16. The Genetic Basis of Development
Central Themes of Developmental Genetics

The general body plan is common to all members of a species and, indeed, is common to many very different species. All mammalian species have four limbs, whereas all insects have six. But all mammals and insects must, in the course of their development, differentiate the anterior from the posterior end and the dorsal from the ventral side. Eyes and legs always appear in the appropriate places. Except for severe disturbances that interfere with development, the basic body plan of a species appears to be quite immune from environmental modification. The study of the basic development of body plan can then be carried out by studying the internal genetic program of the organism without reference to the environment. We should not forget, however, that the study of the genetic determination of these basic developmental processes does not provide us with an explanation of the phenotypic differences between individual members of a species. This chapter focuses on the processes underlying pattern formation, the construction of complex form, and how these processes operate reliably to execute the developmental program for the basic body plan.

The Logic of Building the Body Plan

During the elaboration of the body plan, cells commit to specific cell fates; that is, the capacity to differentiate into particular kinds of cells. The cell fate commitments have to make sense in regard to the location of the cell, because all organs and tissues are made up of many cells and the entire structure of an organ or tissue requires a cooperative division of labor among the participating cells. Thus, somehow, cell position must be identified, and fate assignments must be parceled out among a cooperating group of cellscalled a developmental field.

Positional information is generally established through protein signals that emanate from a localized source within a cell (the initial one-cell zygote) or within a developmental field. This is the molecular equivalent to establishing the rules for geographical longitudes and latitudes. Just as we need longitudes and latitudes to navigate on Earth, cells need positional information to determine their location within a developmental field and to respond by executing the appropriate developmental program. When that positional information has been captured, generally a few intermediate cell types are created within a field. Through further processes of cell division and decision making, a population of cells with the necessary final diversity of fates will be established.

These further processesfate refinementcan be of two types. Sometimes, through asymmetric divisions of one of the intermediate types of cells, descendants are created that have received different regulatory instructions and therefore become committed to different fates. This can be thought of as a cell lineage-dependent mechanism for partioning fates. Often, such fate decisions are made by committeethat is, the fate of a cell becomes dependent on input from, and feedback to, neighboring cells through paracrine signaling mechanisms (see Chapter 15). Such neighborhooddependent decisions are extremely important, because the chemical dialog between cells ensures that all fates have been allocated and that the pattern of allocation is coherent. The cell neighborhood-dependent mechanisms also provide for a certain developmental flexibility. Developmental mechanisms need to be flexible so that an organism can compensate for accidents such as the death of some cell. If some cells are lost through accidental cell death, the normal paracrine intercellular communication is then aborted and the surviving neighbors can become reprogrammed to divide and instruct a subset of their descendants to adopt the fates of the deceased cells. Indeed, the regeneration of severed limbs, as occurs in some animals, is a manifestation of the power of specification versus hard-wired determination in building pattern.

MESSAGE
Cells within a developmental field must be able to identify their geographic locations and make developmental decisions in the context of the decisions being made by their neighbors.

The consequence of the preceding scenario for development is that the process of commitment to a particular fate is a gradual one. A cell does not go in one step from being totally uncommitted, or totipotent, to becoming earmarked for a single fate. Each major patterning decision is, in actuality, a series of events in which multiple cells that are at the same level of fate commitment are, in step-by-step fashion, assigned different fates. As these events unfold, cell proliferation is generally occurring. Thus, if we examine a cell lineagethat is, a family tree for a somatic cell and its descendantswe see that parental cells in the tree are less committed than their descendants.

MESSAGE
As cells proliferate in the developing organism, decisions are made to specify more and more precisely the fate options of cells of a given lineage.

The Major Decisions in Building the Embryo

A variety of developmental decisions are undertaken in the early embryo to give cells their proper identities and to build the body plan. Some of them are simple binary decisions:
Separation of the germ line (the gamete-forming cells) from the soma (everything else).
Establishment of the sex of the organism. (Ordinarily, all cells of the body make the same choice.)

These binary decisions tend to be made at one developmental stage and, as we will see later, are examples of irreversible fate determination.

The other major decisions involve multiple fate options and far more intricate decision-making pathways; they lead to the complex pattern elements of the body plan, composed almost entirely of the somatic cells. Most of them are specification decisions taken by local populations of cells:
Establishment of the positional information necessary to orient and organize the two major body axes of the embryo: anteriorposterior (head to tail) and dorsalventral (back to front).
Subdivision of the embryonic anteriorposterior axis into a series of distinct units called segments, or metameres, and assignment of distinct roles to each segment according to its location in the developing animal.
Subdivision of the embryonic dorsalventral axis into the outer, middle, and inner sheets of cells, called the germ layers, and assignment of distinct roles to each of these layers.
Production of the various organs, tissues, systems, and appendages of the body through the coordinated and cooperative action of localized groups of cells of characteristic segmental and germ-layer origin.

MESSAGE
Among developmental decisions, the simpler ones tend to involve irreversible commitment to one of two options, whereas the more complex ones involve selections among multiple options.

Applying Regulatory Mechanisms to Developmental Decisions

In Chapter 14, we learned the ways that transcriptional regulation of biochemical pathways controls the production of specific proteins at the correct time, in the correct place, and in the correct amounts. In a biochemical pathway, the regulatory "switch" that activates or blocks the synthesis of the enzymes of that pathway is usually some nutrient being supplied to the organism externally. In contrast, in the developmental pathway, the regulatory switch depends on some key molecule that is produced internally by the organism itself: either a molecule synthesized by the very cell that makes the decision or a molecule produced by other cells. In a simple developmental pathway, the concentration of such a key molecule will determine if the "on" or the "off" binary choice is made (Figure 16-1). Above some threshold level, one decision will be taken; below this threshold, the opposite decision will be made. The "off" decision implies that development will proceed along the path that had been programmed by previous decisions in the history of that cell; this is usually called the default pathway. The "on" decision shunts the cell into an alternative pathway.

Many pathways also have a maintenance mode that ensures that the "on" or "off" decision is permanently locked in place. Making a pathway decision and subsequently remembering that decision are both key to cell fate commitment.

When we dissect a developmental pathway, we find that its regulatory decisions might be at any level in the process of transferring information from the gene to the active protein (Figure 16-2). In this chapter, we will encounter this process at levels ranging from transcriptional regulation to protein modification and subunit interactions to control the active protein profiles within cells.

© 1999 by W. H. Freeman and Company. All rights reserved.