| 2000 |
|
YEAR BOOK |
| Hox genes : 'The Molecular Architects' |
Trinity College Dublin
In what manner does DNA, in its capacity to produce proteins, code for the diverse variety of biological body forms which shape our natural world? In 1978, E.B. Lewis, an American geneticist studying mutations in the fruit fly Drosophila , proposed a remarkable concept, which was to be crucial in answering this question. These mutations took the form of gross alterations of the fly's body plan, such as 'Antennapedia' , where legs form in place of antennae (see Figure 1) . He conceptually divided the body plan into eight distinct sections based on characteristic developmental mutations in these areas, arising randomly from time to time in large fly populations. From this, Lewis concluded that these developmental errors must be caused by a mix-up in the functioning of 'master control genes' that instigated the development of the fruit fly's body in defined segments.
To prove his theory, workers in the field quickly set upon isolating the genes which Lewis had proposed existed in the fruit fly. Employing newly developed genetic tools, which allowed sensitive detection of genes expressed in the developing body, these eight master regulators were soon discovered. When a broader spectrum of life was probed for similar control genes, a remarkable and unprecedented discovery was made. The same eight genes, with only minor variations in the genetic code, were present all across the animal world. Literally, from fish to fowl, we share the same master control genes that sculpt the basic body plan.
These genes became known as 'Homeobox', or 'Hox' genes (derived from the term 'homeosis' , meaning the developmental transformation of a body segment). It was subsequently discovered that mammals possess four sets, or 'clusters', of Hox genes as opposed to the single set controlling development in the fruit fly. By studying these gene clusters in other species, it has become clear that their overriding mechanism, as well as their basic genetic codes, have been highly conserved across evolution and time, suggesting an early development in the history of life.
Hox genes act by producing proteins in the developing embryo. These proteins act at the tip of a developmental cascade, turning on their target genes by directly binding to very specific DNA sequences preceding the other gene codes, thus causing these target genes to produce new proteins themselves (see Figure 2) . Like a set of molecular dominoes, they recruit a host of protein messengers that lay down the pattern of the basic body plan. All these developmental molecules are expressed in highly specific concentrations that percolate across regions of the embryo in a gradient which lets every cell know exactly where it is in relation to its neighbours and, more importantly, exactly what type of cell it is to become if it is to effectively participate in the overall scheme of things. But, one must again ask a question: if all animals utilise this common conserved mechanism with the same or similar genes for development, why don't all animals look exactly alike?
The key determining factors are (1) concentration ; (2) location ; (3) timing ; and (4) target gene specificity . Since common species possess these highly similar developmental genes, differences of body shape are generated by evolutionary changes in the concentration or amounts of the Hox proteins produced; the location of their production in the developing embryo; and the timing with which they become active in the body plan. The fourth factor, target gene specificity, crucially affects the former three, for if a given Hox gene sequence is altered by mutation, the resulting Hox protein that is expressed may not bind to its target genes and therefore will not attain the required concentration in a given location or time. Alternately, it may bind to a different target gene than it does in other members of the species. Any such changes result in alterations in the body form. It is rather like cutting a new groove into the surface of an old key, that, whilst it may not open the same door, it may fit perfectly into an entirely different lock. Such subtle changes in any of these factors may result in acute, catastrophic mutations, such as antennapedia , or slight, subtle alterations with no overt consequences for the animal as a whole.
Contact: Gareth Brady, Department of Biochemistry, Trinity College Dublin; E-mail: bradyg@tcd.ie
* Gareth Brady won the 2000 RIA/Irish Times Science Writing Competition. This is an abbreviated version of his winning article. For the full article, see either www.tcd.ie (Biochemistry Department - Awards for the Department), or www.ireland.com/newspaper/science/2000/0605/sci2.htm