One of the most mysterious and ill-understood aspects of animal development is the control of growth: why does each part of the body grow to a precisely defined size? This problem is exemplified in remarkable way in the imaginal discs of Drosophila. By induced somatic recombination, one can, for example,
Dpp Wingless (B) Dpp anterior compartment (A) posterior compertment
Engrailed expression defines posterior compartment
Hedgehog in posterior compartment sends a short- range signal to cells in the anterior compartment
anterior cells at compartment boundary express Dpp that signals at long range
100 mm Figure 22–55Morphogenetic signals created at compartment boundaries in the wing imaginal disc. (A) Creation of
the Dpp signaling region at the anteroposterior compartment boundary through a Hedgehog-mediated interaction between the anterior and posterior cells. In an analogous way, a Notch-mediated interaction between dorsal and ventral cells creates a Wingless (Wnt) signaling region along the dorsoventral boundary. (B) The observed expression patterns of Dpp and Wingless. Although it seems clear that Dpp and Wingless act as morphogens, it is not yet certain how they spread out from their source. Cells in the imaginal disc have been seen to send out long cytonemes that may allow them to sense signals at a distance. Thus, the receiving cell may send its sensors to the source of the signal, instead of the signal moving to the receiving cell. (B, photographs courtesy of Sean Carroll and Scott Weatherbee, from S.J. Day and P.A. Lawrence, Development 127:2977–2987, 2000. With permission from The Company of Biologists.)
create a clonal patch of cells that proliferate more rapidly than the rest of the cells in the developing organ. The clone may grow to occupy almost the whole of the compartment in which it lies, and yet it does not overstep the boundary of the compartment. Astonishingly, its rapid growth has almost no effect on the compartment’s final size, its shape, or even the details of its internal pattern (see Figure 22–54). Somehow, the cells within the compartment interact with one another to determine when their growth should stop, and each compartment behaves as a regulatory unit in this respect.
A first question is whether the size of the compartment is regulated so as to contain a set number of cells. Mutations in components of the cell-cycle control machinery can be used to speed up or slow down the rate of cell division with- out altering the rate of cell or tissue growth. This results in abnormally large numbers of abnormally small cells, or the converse, but the size—that is, the area—of the compartment is practically unchanged. Thus, the regulatory mech- anism seems to depend on signals that indicate the physical distance between one part of the compartment and another, and on cellular responses that some- how read these signals so as to halt growth only when the spacing between the parts has reached its proper value.
This type of growth regulation is strikingly displayed in the intercalary
regeneration that occurs when separate parts of a Drosophila imaginal disc or
of a growing cockroach leg are surgically grafted together. After the graft, the cells in the neighborhood of the junction proliferate and fill in the parts of the pattern that should normally lie between them, continuing their growth until the normal spacing between landmarks is restored (Figure 22–56). The mecha- nisms that bring this about are a mystery, but it seems likely that they are simi- lar to the mechanisms that regulate growth during normal development.
What mechanism could ensure that each little piece of the pattern within a compartment grows to its appropriate size, despite local disturbances in growth rate or starting conditions? The morphogen gradients (of Dpp and Wingless, for example) create a pattern by imposing different characters on cells in different positions. Could it be that the cells in each region can somehow sense how close the spacing of the pattern is—how steep the gradient of change in cell charac- ter—and continue their growth until the tissue is spread out to the right degree?
This idea has been tested by creating clones of cells in the wing disc in which downstream components of the Dpp signaling pathway are misexpressed so as to drive the level of pathway activation either higher or lower than in the neigh- boring cells. From the point of view of the cells, conditions at the boundary of the mutant clone are then equivalent to those produced by a very steep gradient of Dpp. The result is that cells in this neighborhood are stimulated to divide at an increased rate. Conversely, if the level of Dpp signaling is made uniform in the middle region of the developing wing disc, where it would normally be steeply graded, cell division there is inhibited. It seems that the steepness of the gradient does indeed control the rate of proliferation. But if that is so, how do cells sense the steepness of the gradient?
The answer is unknown, but there are strong hints that the mechanism depends on signals generated at cell–cell junctions, where cells with different levels of pathway activation make contact. As discussed in Chapter 19, muta- tions in junctional components such as the scaffold protein Discs-large (Dlg) or the cadherin superfamily member Fat can cause a dramatic failure of growth control, allowing the wing disc to grow far beyond its normal proper size. In the case of Fat, a set of other molecules, including protein kinases called Hippo and
1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 8 9 10 1 2 3 4 5 6 7 8 9 10 intercalation
Figure 22–56Intercalary regeneration.
When mismatched portions of the growing cockroach leg are grafted together, new tissue (green) is
intercalated (by cell proliferation) to fill in the gap in the pattern of leg structures, restoring a leg segment of normal size and pattern.
Warts, have been identified as components of a signaling pathway that leads from Fat at the cell membrane to the control of gene expression in the nucleus. The products of the target genes include the cell-cycle regulator cyclin E and an inhibitor of apoptosis, as well as a microRNA, Bantam, that seems to be an essential part of the growth control mechanism. Despite these tantalizing facts, the mechanisms controlling organ size are still mysterious. If we can discover how they work in Drosophila, we may get some insight into the problem of the control of organ size in vertebrates, where our current perplexity on this funda- mental question is even more profound. For in other aspects of organ develop- ment, as we now discuss, flies and vertebrates are unexpectedly similar at a molecular level, suggesting that their mechanisms of growth control may be similar also.