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Control of Cell Fates by Graded Amounts of Regulators

In a developing tissue, each cell must learn how to contribute to the overall organization of the tissue. Frequently, cells in a particular position within the developing embryo must divide, move, change shape, or make specialized products, whereas other nearby cells do not. In modern developmental biology, the term induction refers to events where one cell population influences the fate of neighboring cells. Figure 15-10 schematically depicts how a series of inductive signals can create several cell types, starting from a population of initially equivalent cells. Induction may create tissue types at specific sites (e.g., formation of a lens near the site at which the retina will grow) or cause changes in the shape of cells at a specific location. For example, changes in the shape of cells in the center but not at the periphery of the neural plate give rise to the neural tube from which our central nervous system develops. Cell orientation is critical, too. If an epithelium produces appendages, such as feathers or bristles, all of them may need to point in the same direction. All these properties of cells are coordinated by integrating signals in the developing organism, and each cell interprets the signals that it receives in light of its previous experience and state of differentiation.

Some extracellular inductive signals move through tissue and hence can act at a distance from the signaling cell; some signals are tethered to the surface of the signaling cell and thus can influence only the immediate neighboring cells. Still other signals are highly localized by their tight binding to components of the extracellular matrix. The transmission rate of a signal depends on the chemical properties of the signal, the properties of the tissue through which it passes, and the ability of cells along the way to take up or inactivate the signal. The distance that an inductive signal can move influences the size and shape of an organ. For instance, the farther a signal that induces neuron formation can move, the more neurons will form.

In this section and those that follow, we will see how quantitative differences in external signals and transcription factors can determine cell fates and properties. We begin by distinguishing two basic mechanisms of inductive signaling and then, by way of example, examine in some detail early stages of Drosophila development. To learn how signals work during cell interactions in development, transgenic animals are used to observe the effects of increasing or decreasing gene function in specific cells. For example, if a cell can send a signal even if a certain gene function is removed, the gene is not required for sending the signal. Removing the same gene function from a cell that normally receives the signal may reveal a requirement of the gene for signal reception or transduction. In this way, even when a novel protein is being studied, it is possible to deduce its place in a signaling pathway. These gene manipulation methods are especially advanced in Drosophila (Figure 15-11) but are increasingly being adapted for other experimental organisms.

Initial population

Initial population

▲ FIGURE 15-10 Simplified model of sequential induction of cell types in an epithelium. Step 1: Starting from a population of equivalent cells (white), an initial event (e.g., cell movements or a polarized signal) creates a second population of cells (tan) that secretes a signal (red arrows). This signal reaches only some of the cells in the adjacent field of cells. Step 2|: The cells capable of receiving and interpreting the red signal now form a new cell type (pink) that secretes a different signal (blue arrows) that moves away from the red cells in both directions. Step 3: The blue signal induces still more cell types (purple and blue). Note that the effect of the blue signal differs, depending on whether it acts on white cells or on tan cells.

▲ FIGURE 15-10 Simplified model of sequential induction of cell types in an epithelium. Step 1: Starting from a population of equivalent cells (white), an initial event (e.g., cell movements or a polarized signal) creates a second population of cells (tan) that secretes a signal (red arrows). This signal reaches only some of the cells in the adjacent field of cells. Step 2|: The cells capable of receiving and interpreting the red signal now form a new cell type (pink) that secretes a different signal (blue arrows) that moves away from the red cells in both directions. Step 3: The blue signal induces still more cell types (purple and blue). Note that the effect of the blue signal differs, depending on whether it acts on white cells or on tan cells.

(a) Ectopic gene expression with spatial/temporal control

A fly gene of interest is linked to a regulated promoter in order to express the gene in a time or place that is not normal. If the overexpression is lethal, no transgenic flies can be obtained (see part [b] for a solution to this problem). A variation is to use a heat-inducible promoter from a "heat shock" gene; a pulse of heat (37° C, 30 min) will cause expression in all cells.

Transgene

Regulated promoter

Gene of interest

(b) Spatially and temporally regulated ectopic gene expression using GAL4

One transgenic fly codes for the yeast transcription factor Gal4 under the control of a tissue-specific promoter. Another carries a transgene that can respond to Gal4 because it contains a UAS sequence to which Gal4 binds. After crossing the two flies, any gene that had been attached to the UAS sequence will fall under the control of Gal4 and be expressed in that specific tissue. This allows each transgenic fly line to survive, even if the activation of the gene will prove lethal in the progeny of the cross.

Transgene 1

Regulated promoter

Transgene 2

^ Gal4-binding UAS Gene of interest ^

(c) Creating mosaic tissues with clones of cells that lack a gene function

Yeast FLP recombinase, acting upon FRT sequences inserted near the centromere, can be used to create clones of homozygous mutant cells in flies that are heterozygous for a recessive mutation. Recombinase is produced at a specified time using a heat-inducible promoter. Just enough recombinase is induced to cause an occasional recombination event. The effects of lost gene function are then assessed.

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