El concepto de estrategia en el aprendizaje de lengua extranjera

Vertebrates are comparatively big animals, and they owe much of their bulk to connective tissues. For excretion, absorption of nutrients, and gas exchange, however, they also require large quantities of various specialized types of epithe- lial surfaces. Many of these take the form of tubular structures created by branch- ing morphogenesis, in which an epithelium invades embryonic connective tissue (mesenchyme) to form a composite organ. The lung is a typical example. It orig- inates from the endoderm lining the floor of the foregut. This epithelium buds and grows out into the neighboring mesenchyme to form the bronchial tree, a system of tubes that branch repeatedly as they extend (Figure 22–92). The same mesenchyme is also invaded by endothelial cells—the lining cells of blood ves- sels—to create the system of closely apposed airways and blood vessels required for gas exchange in the lung (discussed in Chapter 23).

The whole process depends on exchanges of signals in both directions between the growing buds of epithelium and the mesenchyme that they are invading. These signals can be analyzed by genetic manipulation in the mouse. A central part is played by signal proteins of the fibroblast growth factor (FGF) family and the receptor tyrosine kinases on which they act. This signaling path- way has various roles in development, but it seems to be especially important in the many interactions that occur between epithelium and mesenchyme.

Mammals have about 20 different Fgf genes, as compared with three in Drosophila and two in C. elegans. The Fgf that is most important in the lung is Fgf10. This is expressed in clusters of mesenchyme cells near the tips of the growing epithelial tubes, while its receptor is expressed in the epithelial cells

ES cells derived from genetically distinct strain of mice recipient blastocyst clump of ES cells in micropipette holding suction pipette ES cells injected into blastocyst

injected cells become incorporated in inner cell mass of host blastocyst blastocyst develops in foster mother into a healthy chimeric mouse; the ES cells may contribute to any tissue

Figure 22–91Making a chimeric mouse with ES cells. The cultured ES cells can

combine with the cells of a normal blastocyst to form a healthy chimeric mouse, and can contribute to any of its tissues, including the germ line. Thus the ES cells are totipotent.

(A) (B) FGF10 made by cluster of mesenchyme cells FGF10 receptor on bud epithelium cells FGF10 production inhibited by Shh

two new centers of FGF10 production created Sonic hedgehog (Shh) produced by epithelial cells at tip of growing bud

two new buds are formed and the whole process repeats

Figure 22–92Branching morphogenesis of the lung. (A) How FGF10 and Sonic

hedgehog are thought to induce the growth and branching of the buds of the bronchial tree. Many other signal molecules, such as BMP4, are also expressed in this system, and the suggested branching mechanism is only one of several possibilities. (B) A cast of the adult human bronchial tree, prepared by injecting resin into the airways; resins of different colors have been injected into different branches of the tree. (B, from R. Warwick and P.L. Williams, Gray’s Anatomy, 35th ed. Edinburgh: Longman, 1973.)

themselves. FGF10 or its receptor can be knocked out (by the standard tech- niques based on recombination in ES cells). In the resulting knock-out mutant mouse, the whole process of branching morphogenesis then fails—a primary bud of lung epithelium is formed but fails to grow out into the mesenchyme to create a bronchial tree. Conversely, a microscopic bead soaked in FGF10 and placed near embryonic lung epithelium in culture will induce a bud to form and grow out toward it. Evidently, the epithelium invades the mesenchyme only by invitation, in response to FGF10.

But what makes the growing epithelial tubes branch repeatedly as they invade? This seems to depend on a Sonic hedgehog signal that is sent in the opposite direction, from the epithelial cells at the tips of the buds back to the mesenchyme. In mice lacking Sonic hedgehog, the lung epithelium grows and differentiates, but forms a sac instead of a branching tree of tubules. Meanwhile, FGF10, instead of being restricted to small clusters of mesenchyme cells, with each cluster acting as a beacon to direct the outgrowth of a separate epithelial bud, is expressed in broad bands of cells immediately adjacent to the epithe- lium. This finding suggests that the Sonic hedgehog signal may serve to shut off FGF10 expression in the mesenchyme cells closest to the growing tip of a bud, splitting the FGF10-secreting cluster into two separate clusters, which in turn cause the bud to branch into two (see Figure 22–92A).

The branching growth of the epithelium and mesenchyme has to be coordi- nated with development of the associated blood vessels, and the whole process involves a large number of additional signals. Many aspects of the system are still not understood. It is known, however, that Drosophila uses closely related mechanisms to govern the branching morphogenesis of its tracheal system—the tubules that form the airways of an insect. Again, the process depends on the Drosophila FGF protein, encoded by the Branchless gene, and the Drosophila FGF receptor, encoded by the Breathless gene, both operating in much the same way as in the mouse. Indeed, genetic studies of tracheal development in Drosophila have also identified other components of the control machinery, and the Drosophila genes have led us to their vertebrate homologs. Genetic manip- ulations in the mouse have given us the means to test whether these genes have similar functions in mammals too; and to a remarkable extent they do.

Summary

The mouse has a central role as model organism for study of the molecular genetics of mammalian development. Mouse development is essentially similar to that of other vertebrates, but begins with a specialized preamble to form extraembryonic structures such as the amnion and placenta. Powerful techniques have been devised for creation of gene knockouts and other targeted genetic alterations by exploiting the highly regu- lative properties of the cells of the inner cell mass of the mouse embryo. These cells can be put into culture and maintained as embryonic stem cells (ES cells). Under the right culture conditions, ES cells can proliferate indefinitely without differentiating, while retaining the ability to give rise to any part of the body when injected back into an early mouse embryo.

Many general developmental processes, including most of those discussed else- where in the chapter, have been illuminated by studies in the mouse. As just one exam- ple, the mouse has been used to investigate the control of branching morphogenesis. This process gives rise to structures such as lungs and glands, and is governed by exchanges of signals between mesenchyme cells and an invading epithelium. The functions of these signals can be analyzed by gene knockout experiments.