Book Viewer

Short Contents | Full Contents | Other books @ NCBI

Modern Genetic Analysis Chapter 16. The Genetic Basis of Development
The Many Parallels in Vertebrate and Insect Pattern Formation

How universal are the developmental principles uncovered in Drosophila? Until recently, the type of genetic analysis possible in Drosophila was not feasible in most other organisms, at least not without a huge investment to develop comparable genetic tools. However, in the past few years, recombinant DNA technology has provided the tools for addressing the generality of the Drosophila findings (see Genetics in Process 16-5 on the following page). Some of the most spectacular advances have come from studying early mouse development.

Perhaps the most striking case is the similarity between the clusters of mammalian homeobox genes called the Hox complexes and the insect ANT-C and BX-C homeotic gene clusters, now collectively called the HOM-C (homeotic gene complex) (Figure 16-31). The ANT-C and BX-C clusters, which are far apart on chromosome 3 of Drosophila, are in one cluster in more primitive insects such as the flour beetle Tribolium castaneum. This indicates that the typical case in insects is that there is only one homeotic gene clusterHOM-C. Moreover, the genes of the HOM-C cluster are arranged on the chromosome in an order that is colinear with their spatial pattern of expression: the genes at the left-hand end of the complex are transcribed near the anterior end of the embryo; rightward along the chromosome, the genes are transcribed progressively more posteriorly (compare Figure 16-31a and b).

We still do not know why the insect genes are clustered or organized in this colinear fashion, but, regardless of the roles of these features, the same structural organizationclustering and colinearityis seen for the equivalent genes in mammals, which are organized into the Hox clusters (Figure 16-31a). The major difference between flies and mammals is that there is only one HOM-C cluster in the insect genome, whereas there are four Hox clusters, each located on a different chromosome, in mammals. These four Hox clusters are paralogous, meaning that the structure (order of genes) in each cluster is very similar, as if the entire cluster had been quadruplicated in the course of vertebrate evolution. The genes near the left end of each Hox cluster are quite similar not only to each other, but also to one of the insect HOM-C genes at the left end of the cluster. Similar relations hold throughout the clusters. Finally, and most notably, the Hox genes are expressed in a segmental fashion in the developing somites and central nervous system of the mouse (and presumably the human) embryo. Each Hox gene is expressed in a continuous block beginning at a specific anterior limit and running posteriorly to the end of the developing vertebral column (Figure 16-32). The anterior limit differs for different Hox genes. Within each Hox cluster, the leftmost genes have the most anterior limits. These limits proceed more and more posteriorly in the rightward direction in each Hox cluster. Thus, the Hox gene clusters appear to be arranged and expressed in an order that is strikingly similar to that of the insect HOM-C genes (see Figure 16-31b).

The correlations on structure and expression pattern are further strengthened by considerations of mutant phenotypes. In vitro mutagenesis techniques permit efficient gene knockouts in the mouse. Many of the Hox genes have now been knocked out, and the striking result is that the phenotypes of the homozygous knockout mice are thematically parallel to the phenotypes of homozygous null HOM-C flies. For example, the Hoxc-8 knockout causes ribs to be produced on the first lumbar vertebra, L1, which ordinarily is the first nonribbed vertebra behind those vertebrae-bearing ribs (Figure 16-33). Thus, the L1 vertebra is homeotically transformed to the segmental identity of a more anterior vertebra. To use geneticists' jargon, Hoxc-8 has caused a fate shift toward anterior. Clearly, this Hox gene seems to control segmental fate in a manner quite similar to the HOM-C genes, because, for example, the absence of the Drosophila Ubx gene also causes a fate shift toward anterior in which T3 and A1 are transformed to T2.

How can such disparate organismsfly, mouse, humanhave such similar gene sequences? (The same is true for the worm C. elegans.) The simplest interpretation is that the Hox and HOM-C genes are the vertebrate and insect descendants of a homeobox gene cluster present in a common ancestor some 600 million years ago. The evolutionary conservation of the HOM-C and Hox genes is not a singular occurrence. Many examples of strong evolutionary and functional conservation of genes and entire pathways have been uncovered. In Figure 16-34 on the following page, essentially completely conserved pathways for activating the Drosophila DL and mammalian NF k B transcription factors are presented. The Drosophila protein at any step in the DL activation pathway is similar in amino acid sequence to its counterpart in the mammalian NF k B activation pathway. (Don't worry about what the particular proteins do; just appreciate the incredible conservation of cellular and developmental pathways as indicated by the components of the pathway indicated by similarly shaped objects in the diagrams. We do indeed know that DL and NF k B participate in some equivalent developmental decisions.) Indeed, as can be seen from a selection from the known examples (see Table 16-4), such evolutionary and functional conservation seems to be the norm rather than the exception.

MESSAGE
Developmental strategies in animals are quite ancient and highly conserved. In essence, a mammal, a worm, and a fly are put together with the same basic building blocks and regulatory devices. Plus ça change, plus c'est le même chose!

© 1999 by W. H. Freeman and Company. All rights reserved.