Figure 9-9. Combinatorial HoxD gene expression during development and its correspondence to sections of the adult tetrapod limb. Redrawn with permission from (O'Day 2003).

An interesting aspect of the vertebrate limb has to do with how its PD axis is formed and the Hox expression patterns are initiated. A structure called the apical ectodermal ridge (AER) forms as a kind of line that caps the distal edge of the limb bud. The AER has been thought to be a dynamic generative structure, or progress zone, so that as cells divide under the AER, the longer their precursors have been in that region the more they are prepared to make the segments that they do (stylopod, zeugopod, autopod). This seemed to be similar to the model of seashell patterning along a linear progress zone described earlier. Unfortunately, like so many stories of this kind, continued research shows that the story is not so tidy. The AER had been thought to be perhaps a stripe of reaction-diffusion-like process too slow to repeat before the limb becomes mineralized or stops growing for other reasons, but recent evidence suggests that the AER is already prepatterned in miniature, perhaps like the dental arch or tastebud patterning of the tongue, the three major limb segments ready to be "revealed" in the process of growth (Chiang et al. 2001; Duboule 2002; Dudley et al. 2002; Sun et al. 2002).

Wings grow out from the main body axis in flies and butterflies, representing a different kind of limb. AP coordinates are specified by sequential activation of genes called Engrailed (a homeobox TF), and the SFs Hedgehog and Dpp. Only the posterior part of this region expresses Engrailed, which induces Hh. Anterior cells express the Ptc receptor for Hh signal; receipt of this signal induces a line of Dpp expression. DV compartments are separated by dorsal expression of the Apterous homeobox TF, which induces expression of Serrate and Fringe components of the Notch signaling system; Notch receptors are expressed across the whole region but only receive Serrate/Fringe in the posterior part, and that induces in turn a stripe of the Wg (Wingless) SF expression.

Wg, like Dpp, diffuses in both directions from this line, inducing different subsequent expression leading to compartment-specific differentiation. Some of the SFs work across only a few cell diameters, such as Hh, but induce others that can travel more (e.g., up to about 20 for Dpp), in a kind of relay system. Two TFs, Vg and Sd, are expressed in all wing cells and enable other wing-specific differentiation to occur. When these two genes, along with compartment-specific TFs, are activated in the same cell they induce further compartment-specific gene expression, all resulting in compartment-specific combinations of expressed genes.


Budding occurs when a cell or cluster of cells in a tissue begins to proliferate locally and grow outward or inward from the initial tissue layer. Branching occurs if secondary buds form from a primary, and if this occurs repeatedly over time a treelike structure results. The processes are not unique; for example the hand can be viewed as a branched structure coming of the original budlike structure of the limb. We think first of branches and roots in plants, naturally, but similar patterns occur in animals. Branching can occur from an initiation site outward, as in plants, or inward as in the branching lobes and bronchi of lungs. Other examples include the branching of vascular systems, and the development of nephrons in the kidney, the ductal structure in mammary glands, and nerve networks. The branching of the major nerves of the human nervous system is shown in Figure 9-10A, and the circulatory system in Figure 9-10B.

Some branchlike organs are produced by a process known as clefting. Ingrowth of cells from the periphery of a bud can form a wall that divides the bud in two. Along with the formation of buds and branches, these processes can generate many of the structures we see in complex organisms (Hogan 1999). One can view the hand as a clefted as well as a branched structure. A pad forms first, in which the digital ray cartilages form, but then apoptotic processes cleft the spaces between the digits (but not in webbed species).

Branching systems arise in various ways. Some begin developmentally as a single initial indentation or sac (rather than a placode), which divides into a nested hierarchy of internally descendant branches. The first or major divisions of branching systems are often highly stable among individuals, as in the left and right lobes of the mammalian lung or the major arteries, veins, and nerves (which is why anatomy students have to memorize them). Eventually, these systems divide into more numerous and/or highly variable branches like capillaries (which is why anatomy students don't have to memorize them).

Some systems, like the circulation, are closed (branches must connect so that blood can circulate), whereas others, like the lung, are open-ended (branches can diverge ever farther from the original trunk). The mammalian circulatory system forms as an initial plexus of connected vessels and then proliferates by sprouting new vessels and collapsing or destroying others to form the large, deeply branched, but closed system in the adult.Vessels can form "on demand," induced by the release of signals from tissues starved of oxygen—including tumors—so that a branching pattern can often best be characterized by the process that generates it rather than by a map of the final structures.

Some deeply branched systems produce ever more numerous and smaller branches that resemble a fractal phenomenon. This means that the branching pattern is essentially the same no matter at what point you observe it. The developmental process continues to generate new copies of that pattern, though in many cases of ever-smaller absolute size. Mathematical models can mimic such structures, and give a compelling explanation of the type of continual process that generates the pattern, but some patterns that look as if they "must" be fractal really are not literally so (Metzger and Krasnow 1999). Instead, what is most useful is to say that, like the periodic patterning discussed above, a process is at work rather than a specific program for each element in the system. Indeed, because new branches can be induced at least in some systems (blood vessels, plants), this must be so for them.

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