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Modern Genetic Analysis Chapter 16. The Genetic Basis of Development
Additional Aspects of Pattern Formation

The principles delineated in the preceding sections lay out initial fates, but additional mechanisms must be in place to ensure that all aspects of patterning are elaborated. Some of these mechanisms are considered in this section.

Memory Systems for Remembering Cell Fate

Patterning decisions frequently need to be maintained in a cell lineage for the lifetime of the organism. This requirement is certainly true of the segment-polarity and homeotic gene expression patterns that are set up by the AP patterning system. Such maintenance is accomplished through intracellular or intercellular positive feedback loops (Figure 16-27).

In several tissues, positive feedback loops are established in which the homeodomain protein that is expressed binds to enhancer elements in its own gene, ensuring that more of that homeodomain protein will continue to be produced (Figure 16-27a). (This is reminiscent of the positive feedback loop for Sxl splicing in the female developmental pathway, discussed earlier in this chapter.)

The other solution requires cellcell interactions (Figure 16-27b). For example, among the segmentpolarity genes, adjacent cells express the WG and EN proteins. The EN protein is a transcription factor that activates HH in the same cells. (See Table 16-4 on the next page for more information on these proteins and the genes that encode them.) HH is a secreted protein signaling molecule that induces a receptor-mediated signal transduction cascade in the WG cell, including wg (wingless) gene expression and more WG protein to be expressed. WG similarly is a secreted protein that activates en (engrailed)expression in the adjacent cell, inducing more EN protein in that cell.

MESSAGE
Once the fate of a cell lineage is established, it must be remembered.

Ensuring That All Fates Are Allocated: Decisions by Committee

Ultimately, for a developmental field to mature into a functional organ or tissue, cells must be committed in appropriate numbers and locations to the full range of fates that are needed. Cellcell interactions ensure that these proper allocations are made. We should be aware of two types of interactions, both of which operate in the development of the vulva, the opening to the outside of the reproductive tract of the nematode C. elegans (Figure 16-28). One type is the ability of one cell to induce a developmental commitment in one neighbor of many, and the other is the ability of one cell to inhibit its neighbors from adopting its fate.

Vulva development has been studied in detail through the analysis of mutants that have either no vulva or too many. Within the hypoderm (the body wall of the worm), several cells have the potential to build certain parts of the vulva. To make an intact vulva, one of the cells must become the primary vulva cell, and two others must become secondary vulva cells (Figure 16-29a); yet others become tertiary cells that contribute to the surrounding hypoderm (Figure 16-29b).

Initially, all these cells can adopt any of these roles and so are called an equivalence groupin essence, a developmental field. The key to allocating the different roles to these cells is another single cell, called the anchor cell, which lies underneath the cells of the equivalence group (Figure 16-29c). The anchor cell secretes a polypeptide ligand that binds to a receptor tyrosine kinase (RTK) present on all the cells of the equivalence group. Only the cell that receives the highest level of this signal (the equivalence group cell nearest the anchor cell) activates the signal transduction pathway at a sufficient level to activate the transcription factors necessary for that cell to become a primary vulva cell (Figure 16-29d). Thus we can say that the anchor cell operates through an inductive interaction to commit a cell to the primary vulva fate.

Having acquired its fate, the primary vulva cell sends out a different paracrine signal to its immediate neighbors in the equivalence group, inhibiting those cells from similarly interpreting the anchor cell signal to also adopt the primary role. This process of lateral inhibition leads these neighboring cells to adopt the secondary fate. The remaining cells of the equivalence group develop as tertiary cells and contribute to the hypoderm surrounding the vulva. For each of the three cell types that the equivalence group develops into, there is a specific constellation of transcription factors that are activated and that typify the state of the cell: primary, secondary, or tertiary. Thus, through a series of paracrine intercellular signals, a group of equivalent cells can develop into the three necessary cell types.

MESSAGE
Fate allocation can be made through a combination of inductive and lateral inhibitory interactions between cells.

Developmental Pathways Are Composed of Plug and Play Modules

Many developmental pathways are under active investigation in model organisms. From these studies, it is clear that the components of developmental pathways contribute over and over again to the development of a given species. There are rather few examples of a gene product taking part in pattern formation that contributes to only one developmental decision. Instead, bits and pieces of pathways are combined in different ways to determine different outcomes. It is as if, once an effective solution to a particular developmental problem evolved, it was then applied to solve many other problems. This can be thought of as a molecular correlate of the general evolutionary point of view that new structures arise by modifications and adaptations of existing structures rather than by the invention of something totally new.

MESSAGE
Components of one developmental pathway are also found in many others but are often mixed and matched as if they are reusable cartridges.

Typically, a part of a pathway has different inputs, in regard to the signals that regulate it, and sometimes the outputs are different as well (Figure 16-30). As an example of different inputs, the dpp (decapentaplegic) gene, whose complex structure was described in Chapter 14, is regulated during embryonic DV pattern formation by the DL transcription factor, whereas, during visceral mesoderm development, it is regulated by the UBX transcription factor. In regard to different outputs, in maintenance of proper segment-polarity gene expression and cell fates, for example, the ENHH component of the positive feedback loop activates WG in adjacent cells (described earlier). During the larval development of the Drosophila adult wing, the ENHH component activates a different secreted signaling proteinDPPin cells adjacent to ENHH expression. As another example of output differences, the DPP signal transduction pathway leads to activation of completely different transcription factors in DV patterning, wing, and visceral mesoderm development. Indeed, the complicated regulatory element structure common to many higher eukaryotic genes is probably a necessary consequence of the need to respond to many different tissue-specific inputs.

MESSAGE
Differences in the developmental context of different cell lineagesthat is, the transcription factors active in these cellspermit different inputs to, and outputs from, a given developmental circuit.

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