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Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000.
Developmental Biology. 6th edition.
Show detailsOne of the most exciting findings of the past decade has been the existence not only of homologous regulatory genes, but also of homologous signal transduction pathways (Zuckerkandl 1994; Gilbert 1996; Gilbert et al. 1996). Many of those pathways have been mentioned earlier in this book. They are composed of homologous proteins arranged in a homologous manner. In this respect, the homology is similar to that of a human forearm and a seal flipper. The parts—the proteins—are homologous, and the structures they make up-the pathways—are homologous.
Homologous pathways form the basic infrastructure of development. The targets of these pathways may differ, however, among organisms. For example, the Dorsal-Cactus pathway used in Drosophila for specifying dorsal-ventral polarity is also used by the mammalian immune system to activate inflammatory proteins (see Figure 9.38). This does not mean that the Drosophila blastoderm is homologous to the human macrophage. It merely means that there is a very ancient pathway that predates the deuterostome-protostome split, and that this pathway can be used in different systems. The pathways (one in Drosophila, one in humans) are homologous; the organs they form are not.
Another ancient pathway is the RTK pathway (see Figure 6.14). In Drosophila, the determination of photoreceptor 7 is accomplished when the Sevenless protein (on the presumptive photoreceptor 7) binds to the Bride of sevenless (Boss) protein on photoreceptor 8. This interaction activates the receptor tyrosine kinase of the Sevenless protein to phosphorylate itself. The Drk protein then binds to these newly phosphorylated tyrosines through its Src-homology-2 (SH2) region and activates the Son of sevenless (SOS) protein. This protein is a guanosine nucleotide exchanger and exchanges GDP for GTP on the Ras1 G protein. This activates the G protein, enabling it to transmit its signal to the nucleus through the MAP kinase cascade (Figure 22.12). This same system has been found to be involved in the determination of the nematode vulva, the mammalian epidermis, and the Drosophila terminal segments. The similarity in these systems is so striking that many of the components are interchangeable between species. The gene for human GRB2 can correct the phenotypic defects of sem-5-deficient nematodes, and the nematode SEM-5 protein can bind to the phosphorylated form of the human EGF receptor (Stern et al. 1993). Thus, in the ectoderm of one organism, the RTK pathway may activate the genes responsible for proliferation. But in another organism, the same pathway may activate the genes responsible for making a photoreceptor. And in a third organism, the pathway activates the genes needed to construct a vulva.
Figure 22.12
The widely used RTK pathway. The outline of the pathway is shown below the diagram, along with the names of its elements in different species. The ligand can be a soluble protein (as in EGF) or a membrane-bound protein on another cell (as in the Bride (more...)
Pathways undergo descent with modification, too. This is readily seen in the Wnt pathway that we have discussed through-out the book. Figure 22.13 shows how the Wnt pathway is used in several different organisms. The pathways are homologous, but not identical. They are thought to have originated in a common ancestral pathway that predated the deuterostome-protostome split.
Figure 22.13
Three modifications of the Wnt pathway. Each pathway proceeds vertically. The cells secreting the Wingless protein are labeled (anterior cells in the Drosophila parasegment, the P2 cell in C. elegans). The responding cells are shown beneath them (posterior (more...)
Earlier in this chapter, we discussed genes such as Pax6 and tinman that appear to have had their developmental functions before the protostome-deuterostome split. We have also discussed homologous pathways that may or may not be used in similar structures. However, there appear to be some pathways that are used to form the same structure in all animals. When homologous pathways made of homologous parts are used for the same function in both protostomes and deuterostomes, they are said to have deep homology (Shubin et al. 1997).
Instructions for forming the central nervous system
One example of deep homology has already been discussed in earlier chapters. First, as seen in Chapter 10, the chordin/BMP4 pathway demonstrates that in both vertebrates and invertebrates, chordin/Short-gastrulation (Sog) inhibits the lateralizing effects of BMP4/Decapentaplegic (Dpp), thereby allowing the ectoderm protected by chordin/Sog to become the neurogenic ectoderm. These reactions are so similar that Drosophila Dpp protein can induce ventral fates in Xenopus and can substitute for the Sog protein (Holley et al. 1995).
In addition to this central inhibitory reaction of chordin/Sog inhibiting BMP4/Dpp, there are other reactions that add to the deep homology of the instructions for forming the protostome and deuterostome neural tube. For instance, the spread of Dpp in Drosophila is aided by Tolloid, a metalloprotease that degrades Sog. The gradient of Dpp concentration from dorsal to ventral is created by the opposing actions of Tolloid (increasing Dpp) and Sog (decreasing it) (Figure 22.14; Marqués et al. 1997). In Xenopus and zebrafish, the homologues of Tolloid—Xolloid and BMP1, respectively—have the same function. They degrade chordin. The gradient of BMP4 from ventral to dorsal is established by the antagonistic interactions of Xolloid or BMP1 (increasing BMP4) and chordin (decreasing BMP4) (Blader et al. 1997; Piccolo et al. 1997). Thus, it appears that nature may have figured out how to make a nervous system only once. The protostome and deuterostome nervous systems, despite their obvious differences, seem to be formed by the same set of instructions.
Figure 22.14
Homologous pathways specifying neural ectoderm in protostomes (Drosophila) and deuterostomes (Xenopus). Both pathways involve a source of chordin/Sog (the organizer in Xenopus, the presumptive neural ectoderm in Drosophila) and a source of BMP4/Dpp (the (more...)
Limb formation
It is also possible that nature has only one set of instructions for forming limbs (Shubin et al. 1997). Nothing could be a better example of analogy than vertebrate and insect legs. Fly limbs and vertebrate limbs have little in common except their function. They have no structural similarities. Insect legs are made of chitin and have no inner skeleton. They are formed by the telescoping out of ectodermal imaginal discs (see Chapter 18). Vertebrate limbs, on the other hand (no pun intended), have no chitin, but possess a bony endoskeleton. These limbs are created by the interaction of ectoderm and mesoderm (see Chapter 16). However, the genetic instructions to form these two distinctly different types of limbs are extremely similar.
As we have seen, Sonic hedgehog is usually expressed in the posterior part of the vertebrate limb bud. If it is expressed in the anterior part of the bud, mirror-image duplications arise (see Figure 16.19; Riddle et al. 1993). In the Drosophila wing or leg imaginal disc, the Hedgehog protein is expressed in the posterior portion of the disc. If it is expressed anteriorly, mirror-image duplications of the wing will form (Figure 22.15; Basler and Struhl 1993; Ingham 1994). Furthermore, certain genes regulated by the Hedgehog proteins have been conserved as well (Marigo et al. 1996). Thus, the anterior-posterior axis appears to be specified in the same way in vertebrate and in insect limbs. The dorsal-ventral axis also appears to be specified similarly. The ventral limb compartments of both insects and vertebrates appear to be specified by the expression of the engrailed gene (Davis et al. 1991; Loomis et al. 1996), while the dorsal compartment is defined by apterous (in insects) or its relative Lmx1 (in vertebrates) (Figure 22.16).
Figure 22.15
Homology of process in the formation of the anterior-posterior axes in Drosophila and chick appendages. A chick limb bud expresses Sonic hedgehog in its posterior region. If Sonic hedgehog is also expressed in an anterior region, the limb develops a mirror-image (more...)
Figure 22.16
Deep homology of the limbs. The same set of proteins is used to establish the polarity of limbs in both deuterostomes (chick) and protostomes (Drosophila). The top panels represent chick limb buds with the dorsal region on top and the apical ectodermal (more...)
The formation of the proximal-distal axis also proceeds similarly in vertebrates and invertebrates. In insects, the wing margin forms at the border between the dorsal cells and the ventral cells. The dorsal cells express Apterous protein, and this activates the expression of Fringe. The interaction of the Fringe protein with the ventral cells leads to the growth of the wing blade outward from the body wall. Unexpectedly, a very similar cascade induces the outgrowth of the vertebrate limb. The apical ectodermal ridge (AER) forms at the junction of the dorsal cells with the ventral cells. The dorsal cells express Radical fringe, a vertebrate homologue of the Fringe protein. This protein is critical in forming the AER. It is interesting that the ways in which these proteins become localized differ enormously between these phyla. Radical fringe, for instance, is induced by fibroblast growth factors, and it induces the AER to produce more fibroblast growth factors for the outgrowth of the limb. Fibroblast growth factors play no role in insect limb development. Yet, the instructions for limb outgrowth and polarity appear to be essentially the same in insects and vertebrates. Nature may have evolved the mechanism to form a limb only once, in the PDA, and both arthropods and vertebrates use modifications that process to this day.
- Homologous Pathways of Development - Developmental BiologyHomologous Pathways of Development - Developmental Biology
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