Hox Genes
How does retinic acid affect Hox gene expression?
During early embryonic development, retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo.[2] It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. [3] The key role of retinoic acid in embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin used for treatment of cancer and acne. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and retinoic acid itself, also have teratogenic potential by this same mechanism. The molecular basis for the interaction between retinoic acid and the Hox genes has been studied by using deletion analysis in transgenic mice carrying constructs of lacZ reporter genes. Such studies have identified functional RAREs within flanking sequences of some of the most 3' Hox genes (including Hoxa1, Hoxb1, Hoxb4, Hoxd4), suggesting a direct interaction between the genes and retinoic acid. These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes.[5]
How do the positions of segmentally repeated structures relate to patterns of expression in Hox genes?
Expression pattern along the anterior-posterior (head to tail) axis that corresponds to the relative location of their genes within the Hox gene cluster. Sequence conservation The homeodomain protein motif is highly conserved across vast evolutionary distances. In addition, homeodomains of individual Hox proteins usually exhibit greater similarity to homeodomains in other species than to proteins encoded by adjacent genes within their own Hox cluster. These two observations led to the suggestions that Hox gene clusters evolved from a single Hox gene via tandem duplication and subsequent divergence and that a prototypic Hox gene cluster containing at least seven different Hox genes was present in the common ancestor of all bilaterian animals
What are the similarities between homeotic complex in flies and Hox genes in mice? How are they different?
Homeotic Genes After the segmentation genes have been activated, homeotic genes determine which appendages and other structures that will be present in each segment. Flies with homeotic mutations may have two pairs of wings or have legs located where antennae should be located. The gene products of homeotic genes are transcription factors. They bind to DNA and initiate transcription. Homeotic genes have been found in many other eucaryotic species as diverse as yeast and humans. All of these species contain the same 180-nucleotide sequence called a homeobox. The remainder of the gene is variable. The part of the protein produced by the homeobox portion of the gene binds to DNA. The variable part of the protein determines which genes are turned on. The protein products of one homeotic gene may turn on the next homeotic gene creating a sequence of gene activation. The homeotic genes of Drosophila are located on one chromosome but in mice and humans, they are located on four different chromosomes. In all of the species the homeotic genes are activated in the same order. Homeotic genes that are activated first control development in the anterior portion of the animal. Homeotic genes that are activated later control development in regions that are posterior to those controlled by genes activated earlier.
How can the function of Hox genes in vertebrates be studied?
Homeotic mutations Incorrect expression of Hox genes can lead to major changes in the morphology of the individual. Homeotic mutations were first identified in 1894, when William Bateson noticed that floral stamens occasionally appeared in the wrong place; he found four example flowers in which the stamens would grow in the place where petals normally grow. In the late 1940s, Edward Lewis began studying homeotic mutation on Drosophila melanogaster which caused bizarre rearrangements of body parts. Mutations in the genes that code for limb development can cause deformity or lead to death. For an example, mutations in the Antennapedia gene cause legs instead of the antenna to develop on the head of a fly.[23] Another famous example in the Drosophila melanogaster is the mutation of the Ultrabithorax Hox gene, which specifies the 3rd thoracic segment. Normally, this segment displays a pair of legs and a pair of halteres (a reduced pair of wings used for balancing). In the mutant lacking functional Ultrabithorax protein, the 3rd thoracic segment now expresses the same structures found on the segment to its immediate anterior, the 2nd thoracic segment, which contains a pair of legs and a pair of (fully developed) wings. These mutants sometimes occur in wild populations of flies, and it was these mutants that led to the discovery of Hox genes.
What is a teratogen?
Teratogen: Any agent that can disturb the development of an embryo or fetus. Teratogens may cause a birth defect in the child. Or a teratogen may halt the pregnancy outright. The classes of teratogens include radiation, maternal infections, chemicals, and drugs.
Are major structures affected in Hox gene single knockouts?
The Hox genes are a set of transcription factor genes that exhibit an unusual property: They provide a glimpse of one way in which gene expression is translated into the many different forms that animals (metazoans) exhibit. For the most part, the genome seems to be a welter of various genes scattered about randomly, with no order present in their arrangement on a chromosome—the order only becomes apparent in their expression through the process of development. The Hox genes, in contrast, seem like an island of comprehensible structure. These are genes that specify segment identity—whether a segment of the embryo will form part of the head, thorax, or abdomen, for instance—and they are all clustered together in one (usually) tidy spot. Within that cluster, there is even further evidence of order. Knocking out individual Hox genes in Drosophila causes homeotic transformations—in other words, one body part develops into another. A famous example is the Antennapedia mutant, in which legs develop on the fly's head instead of antennae. The Hox genes are early actors in the cascade of interactions that enable the development of morphologically distinct regions in a segmented animal. 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. There are several differences between the mouse and fly Hox genes, however. 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. Another difference is that, in the mouse, there are four banks of Hox genes: HoxA, HoxB, HoxC, and HoxD. 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. 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. In the fly, the situation is much simpler. 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 vertebrates, though, each segment has at least two, and in some cases four, Hox genes that may be involved in its development. As a result, there is the possibility of redundancy.
