Animals require specialized types of epithelial surfaces for many functions, including excretion, absorption of nutrients, and gas exchange. Where large surfaces are required, they are often organized as branching tubular structures. The lung is an example. It originates from epithelial buds that grow out from the floor of the foregut and invade neighboring mesenchyme to form the bronchial tree, a system of tubes that branch repeatedly as they extend. Endothelial cells that form the lining of blood vessels invade the same mesenchyme, thereby creating a system of closely apposed airways and blood vessels, as required for gas exchange in the lung (Figure 21–52). This whole process of branching morphogenesis depends on signals that pass in both directions between the growing epithelial buds and the mesenchyme. Genetic studies in mice indicate that FGF proteins and their receptor tyrosine kinases play a central part in these signaling processes. FGF signaling has various roles in development, but it is especially important in the many interactions that occur between a developing epithelium and mesenchyme. Figure 21–52 The airways of the lung,
In the case of lung development, FGF10 is expressed in clusters of mesen-shown in a cast of the adult human bronchial tree. resins of different colors chyme cells that lie near the tips of the growing epithelial tubes, and its receptor is expressed in the invading epithelial cells. In FGF10-deficient mutant mice, a pri of the tree of airways. (From r. Warwick mary bud of lung epithelium is formed but fails to grow out into the mesenchyme and p.L. Williams, Gray’s anatomy, 35th ed.
to create a branching bronchial tree. Conversely, a microscopic bead soaked in edinburgh: Longman, 1973.) two new centers of
FGF10 made by cluster of mesenchyme cells cells at tip of
FGF10 and placed near embryonic lung epithelium in culture will induce a bud to form and grow out from the epithelium toward the bead. Evidently, the epithelium invades the mesenchyme only by invitation, in response to FGF10.
But what makes the growing epithelial tubes of the lung branch repeatedly as they invade the mesenchyme? This depends 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, as shown in Figure 21–53. In mice lacking Sonic hedgehog, the lung epithelium grows and differentiates, but it forms a sac instead of a branching tree of tubules.
FGF signaling acts in a remarkably similar way in the formation of the air-exchange system of insects, which consists of a pattern of fine, air-filled channels called tracheae and tracheoles. These originate from the epidermis covering the surface of the body and extend inward to invade the underlying tissues, branching and narrowing as they go (Figure 21–54). The FGF acts on cells at the tips of the advancing tracheae, causing them to extend filopodia and migrate toward the source of the FGF signal. Because the tip cells remain connected to the remainder of the tracheal epithelium, the pulling force that they generate elongates the tracheal tube.
Initially, the pattern of FGF production in fly embryos is defined by the D-V and A-P patterning systems discussed earlier. In later stages of development, however, FGF expression is induced by transcription regulators called hypoxia-inducible factors (HIFs) that are activated by hypoxia (low oxygen levels). In this way, hypoxia stimulates the formation of finer and finer and more extensively branched trachea, until the oxygen supply is sufficient to stop the process. Hypoxia and HIFs have similar roles in vertebrates, especially in the development of blood vessels, as we shall see in the next chapter.