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Lateral inhibition signals prevent duplication of unique cell types m

Integration of signals allows cells to adjust to their neighbors and to change with time

▲ FIGURE 15-1 Signaling systems and cell responses. Cells are vibrantly alert detectors, sensing and interpreting information constantly to adjust to the environment ( 1) and coordinate activities with surrounding cells. A cell can respond to signals by changing the genes that it transcribes, altering the cell surface, modifying proteins and enzyme activities, moving materials between compartments, revamping its cytoskeleton, migrating, or dying. A modest number of signaling systems constitutes a core toolbox. Each system is used repeatedly in different organisms, in different tissues, and at different times. Signals are crucial in building multicellular organisms, where different cell types are created by controlled signal transmission and reception. Cells can become different, depending on the amount of a signal ( 2|), with a larger amount giving rise to one cell fate and a smaller amount to another. New boundaries form between cells of different types, creating tissues and demarcations within tissues. Different cell types are created by combinations of transcription factors (3). Inhibitory signals emitted by cells undergoing a differentiation step can prevent nearby cells from making the same decision (4|), thus preventing duplication of structures. Cells generally integrate many signals in deciding how to proceed ( 5).

its memory, especially in the course of development and cell differentiation (Figure 15-1). We begin by looking at various techniques that are beginning to provide a global view of signal-induced responses. In particular, we describe how the determination of whole-genome transcription patterns is a source of new insights into responses to signals. We then consider cell responses to certain environmental perturbations in Section 15.2. The next section introduces the concept of graded regulators that cause different cell responses, depending on their concentration. This type of system allows cells at different distances from the source of a regulatory molecule to become different types of cells. We examine how such regulation creates boundaries within an epithelium in early Drosophila development, with cells on one side of the border taking one path of differentiation and those on the other side taking another. The creation of other boundaries by graded transcriptional activators and graded extracellular signals is discussed in Sections 15.4 and 15.5, respectively. As borders form, cells reinforce their decisions by signaling across the borders so that compatible adjacent structures form. As illustrated by the examples in Section 15.6, such signaling can either promote or inhibit particular developmental changes in adjacent cells. In the final section, we take a closer look at how signals are integrated and controlled in different cells.

Although the number of signaling pathways encountered in this chapter and others may seem overwhelming, there are actually a relatively small number of distinct pathways for transducing external signals. Primary among them are the in-

tracellular signal-transduction pathways activated by the various receptor classes listed in Table 14-1. In addition, cell-cell and cell-matrix adhesions mediated by cadherins and integrins can initiate intracellular signaling pathways (Chapter 6). The informational complexity needed to create many cell types and cell properties comes from combining signals. Elucidation of the underlying principles and mechanisms relevant to all signaling pathways forms the foundation for understanding how cells integrate signals to achieve a particular identity or other response.

Experimental Approaches for Building a Comprehensive View of Signal-Induced Responses

Several technical advances are helping investigators to discern the totality of the cellular response to signals. Perhaps the most significant advance is the sequencing of whole genomes from various organisms and subsequent analysis to identify individual genes and analyze their functions. The data amassed in these genome projects have led to the development of techniques for monitoring the effects of a signal on the expression of the entire gene set. Using gene-inactivation methods discussed in Chapter 9, researchers can mutate specific genes encoding various components of signaling pathways. The phenotypic effects of such mutations often provide clues about the functions of pathway components and the order in which they function. In vitro studies on signaling in a variety of differentiated cell types and even complex tissues are now possible because of recent improvements in cell- and tissue-culture methods. Certain signal-induced responses can be monitored in living cells with the use of various fluorescent agents and the observation of cells in a fluorescence microscope. For instance, this technique can reveal changes in the amounts and localization of specific proteins, as well as fluctuations in H+ or Ca2+ concentrations in the cytosol (see Figures 5-46 and 5-47). Development of additional fluorescent indicator dyes will allow monitoring of other molecules in living cells.

Genomic Analyses Show Evolutionary Conservation and Proliferation of Genes Encoding Signals and Regulators

In Chapter 9, we considered the difficulty and ambiguity in identifying genes within genomic sequences, especially in higher organisms. Despite the limitations, genomic analyses have been sources of exciting and sometimes surprising insights or have confirmed earlier conclusions based on the results of other types of studies.

First, the total number of protein-coding genes does not correlate in any simple way with standard conceptions about animal complexity (see Figure 9-34). Humans, for instance, have only about 1.75 times as many genes as the roundworm Caenorhabditis elegans. Likewise, C. elegans has about 1.4 times as many genes as the fruit fly Drosophila, which exhibits a much more complex body plan and more complex behavior.

Second, genomic comparisons support the conclusion based on two decades of developmental genetics research that many regulatory genes whose encoded proteins control tissue differentiation, organogenesis, and the body plan have been conserved for hundreds of millions of years. For example, the Pax6 gene is employed in eye development in enormously diverse organisms, such as clams, flies, and humans, and the tinman gene is necessary for heart development in flies and humans. As discussed in Section 15.4, the Hox gene cluster controls head-to-tail organization of the body in almost all animals examined to date. Because of the conservation of genes and proteins, the results of experiments on one organism are useful guides for research on other organisms. Indeed much of human biology and medicine has been and continues to be built on knowledge gained from a broad spectrum of experimental systems.

Third, despite the considerable commonality of genes and proteins among different animals, genomic analyses suggest that about 30 percent of the genes of each animal organism are unique to that animal. The invertebrates Drosophila and C. elegans have in common certain genes that are not recognizable in any of the other genomes analyzed to date. Flies and worms are believed to have a common ancestor that arose from an even more ancient ancestor in common with vertebrates. If this view is correct, any genes present in flies and humans could be expected to be present in worms; likewise, any genes common to worms and humans would presumably be present in flies. Recent work has revealed that all three species have about 1500 genes in common, as expected (Figure 15-2). Contrary to expectations, however, about 1250 genes common to humans and flies are not found in worms, and about 500 genes common to humans and worms are not found in flies. Thus organism-specific gene loss occurred in the evolution of C. elegans and Drosophila subsequent to the time when the invertebrate and vertebrate lineages diverged.

Fourth, as noted in preceding chapters, duplication of certain protein-coding genes and subsequent divergence in the course of evolution have given rise to gene families. The members of a gene family and corresponding protein family have close but nonidentical sequences. Genomic analysis and findings from other studies show that the number of members in a particular protein family varies in different species. For instance, the transforming growth factor ft family of secreted signaling proteins has 28 members in humans but only 6 in flies and 4 in worms. The semaphorins, which are signals for neural development, form a 22-member family in humans; flies have 6 members and worms have 2. Such proliferation of genes could give rise to signaling proteins that can move different distances through tissue or differ in other properties. Alternatively, the members of a gene family may be differently regulated, thus allowing rather similar proteins to be produced at different times and places. Both types of variation exist, and both allow a moderate number of types of signals to serve a multitude of purposes.

I I Unknown I I Miscellaneous function I I Cell and tissue structure I I Motility

I I Transport and trafficking

Protein folding I I Signaling and regulation I I DNA transcription Metabolism

I I Unknown I I Miscellaneous function I I Cell and tissue structure I I Motility

I I Transport and trafficking

Protein folding I I Signaling and regulation I I DNA transcription Metabolism

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