SUMMARY

In Chapter 11, we mentioned the quip from Jacques Monod and François Jacob that “anything found to be true of E. coli must also be true of Elephants.”2 Now that we have seen the regulatory processes that build worms, flies, mice, and elephants, would we say that they were right? If Monod and Jacob were referring to the principle that gene transcription is controlled by sequence-specific regulatory proteins, we have seen that the bacterial Lac repressor and the fly Hox proteins do indeed act similarly. Moreover, their DNA-binding proteins have the same type of motif. The fundamental insights that Jacob and Monod had concerning the central role of the control of gene transcription in bacterial physiology and that they expected would apply to cell differentiation and development in complex multicellular organisms have been borne out in many respects in the genetic control of animal development.

Many features in single-celled and multicellular eukaryotes, however, are not found in bacteria and their viruses. Geneticists and molecular biologists have discovered the functions of introns, RNA splicing, distant and multiple cis-acting regulatory elements, chromatin, alternative splicing, and, more recently, miRNAs. Still, central to the genetic control of development is the control of differential gene expression.

This chapter has presented an overview of the logic and mechanisms for the control of gene expression and development in fruit flies and a few other model species. We have concentrated on the toolkit of animal genes for developmental processes and the mechanisms that control the organization of major features of the body plan—the establishment of body axes, segmentation, and segment identity. Although we explored only a modest number of regulatory mechanisms in depth, and just a few species, similarities in regulatory logic and mechanisms allow us to identify some general themes concerning the genetic control of development.

  1. Despite vast differences in appearance and anatomy, animals have in common a toolkit of genes that govern development. This toolkit is a small fraction of all genes in the genome, and most of these toolkit genes control transcription factors and components of signal-transduction pathways. Individual toolkit genes typically have multiple functions and affect the development of different structures at different stages.

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  2. The development of the growing embryo and its body parts takes place in a spatially and temporally ordered progression. Domains within the embryo are established by the expression of toolkit genes that mark out progressively finer subdivisions along both embryonic axes.

  3. Spatially restricted patterns of gene expression are products of combinatorial regulation. Each pattern of gene expression has a preceding causal basis. New patterns are generated by the combined inputs of preceding patterns. In the examples presented in this chapter, the positioning of pair-rule stripes and the restriction of appendage-regulatory-gene expression to individual segments requires the integration of numerous positive and negative regulatory inputs by cis-acting regulatory elements.

    Post-transcriptional regulation at the RNA level adds another layer of specificity to the control of gene expression. Alternative RNA splicing and translational control by proteins and miRNAs also contribute to the spatial and temporal control of toolkit-gene expression.

    Combinatorial control is key to both the specificity and the diversity of gene expression and toolkit-gene function. In regard to specificity, combinatorial mechanisms provide the means to localize gene expression to discrete cell populations by using inputs that are not specific to cell type or tissue type. The actions of toolkit proteins can thus be quite specific in different contexts. In regard to diversity, combinatorial mechanisms provide the means to generate a virtually limitless variety of gene-expression patterns.

  4. The modularity of cis-acting regulatory elements allows for independent spatial and temporal control of toolkit-gene expression and function. Just as the operators and UAS elements of prokaryotes and simple eukaryotes act as switches in the physiological control of gene expression, the cis-acting regulatory elements of toolkit genes act as switches in the developmental control of gene expression. The distinguishing feature of toolkit genes is the typical presence of numerous independent cis-acting regulatory elements that govern gene expression in different spatial domains and at different stages of development. The independent spatial and temporal regulation of gene expression enables individual toolkit genes to have different but specific functions in different contexts. In this light, it is not adequate or accurate to describe a given toolkit-gene function solely in relation to the protein (or miRNA) that it encodes because the function of the gene product almost always depends on the context in which it is expressed.