In flies, one gene can be mutated, resulting in a haltere being transformed into a wing, or an antenna turning into a leg in the mouse, two to four genes must be simultaneously removed to get a similar complete transformation. This phenomenon is also one reason why homeotic mutations in vertebrates are so rarely seen. That is, in order to see what the third Hox gene does in the cluster, for instance, you need to carry out a paralogous deletion that destroys the function of HoxA3, HoxB3, and HoxD3 (there is no HoxC3) to assess the phenotype. Ultimately, all of the paralogous genes need to be knocked out.
They also complicate analyses by indicating that knocking out the Hox genes one at a time in the mouse will result in cases in which no phenotype or a partial phenotype will be seen, even when the gene has an important role to play in that segment. These results tell us that a combination of Hox genes is required for the proper development of the first cervical vertebra. In fact, in this instance, it is thought that the initial mesodermal tissue for the bone is so thoroughly respecified that it fuses completely with the skull instead, becoming part of the base of the skull. However, knocking out both HoxA3 and HoxD3 shows that HoxA3 is important after all without it, the first neck vertebra doesn't form. When HoxD3 is mutated all by itself, there is a serious abnormality here, the first neck vertebra has a partial fusion with the base of the skull. Notice in Figure 1 that HoxA3 has a paralog, or copy, called HoxD3, which is expressed in a very similar place. Deleting HoxA3 has no detectable effects on that joint either its influence is too subtle to measure, it affects some other aspect of cervical specification, or it has a partner gene that takes over its job in its absence. As a result, there is the possibility of redundancy.įor instance, in mice, the HoxA3 gene is expressed in the anterior cervical vertebrae, near the region where the first neck vertebra articulates with the skull. In vertebrates, though, each segment has at least two, and in some cases four, Hox genes that may be involved in its development.
Because each segment more or less expresses only one Hox gene, mutating or knocking out a single Hox gene will have an effect on the corresponding body segment. In the fly, the situation is much simpler. This means that there could be a Hox code, in which identity can be defined with more gradations by mixing up the bounds of expression of each of the genes.
Vertebrates have these parallel, overlapping sets of Hox genes, which suggest that morphology could be a product of a combinatorial expression of the genes in the four Hox clusters. Another difference is that, in the mouse, there are four banks of Hox genes: HoxA, HoxB, HoxC, and HoxD. One obvious difference is that there are more Hox genes on the 5' side of the mouse segment these correspond to expression in the tail, and flies do not have anything homologous to the chordate tail. There are several differences between the mouse and fly Hox genes, however. Vertebrates, including mice, have Hox genes that are homologous to those of the fly, and these genes are clustered in discrete locations with a 3'-to-5' order reflecting an anterior to posterior order of expression. Now examine the mouse portion of Figure 1. Indeed, the activation of a Hox gene from the 3' end is one of the earliest triggers that lead the segment to develop into part of the head. The Hox genes are early actors in the cascade of interactions that enable the development of morphologically distinct regions in a segmented animal. A famous example is the Antennapedia mutant, in which legs develop on the fly's head instead of antennae. Knocking out individual Hox genes in Drosophila causes homeotic transformations-in other words, one body part develops into another. The gene found on the left or 3' end of the DNA strand, denoted lab (labial), is expressed in the head on the other hand, the gene at the right end of the DNA strand, Abd-B (Abdominal-B), is expressed at the end of the fly's abdomen. As shown, in Drosophila there are eight Hox genes in a row, and the genes' order within that row reflects their order of expression in the fly body. To better understand the arrangement and role of Hox genes, take a look at the Drosophila portion of Figure 1.
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