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Scientific American Paper The Molecular Architects of Body Design Putting a human gene into a fly may sound like the basis for a science fiction film, but it demonstrates that nearly identical molecular mechanisms define body shapes in all animals by William McGinnis and Michael Kuziora ll animals develop from a single tems that mold our form, we humans Antennapedia adults are rare excep- fertilized egg cell that goes may be much more similar to our far tions, because most mutations in ho- A through many rounds of divi- distant worm and insect relatives than meotic genes cause fatal birth defects sion, often yielding millions of embry- we might like to think. So similar, in in Drosophila. Nevertheless, even those onic cells. In a dazzling and still myste- fact, thatÑas our work has shownÑcu- dying embryos can be quite instructive. rious feat of self-organization, these rious experimenters can use some hu- For instance, Ernesto Sanchez-Herrero cells arrange themselves into a com- man and mouse Hox genes to guide the and Gines Morata of the Independent plete organism, in which bone, muscle, development of fruit-ßy embryos. University of Madrid found that elimi- brain and skin integrate into a harmo- The story of these universal molecu- nation of three genes in the bithorax nious whole. The fundamental process lar architects actually begins with the complexÑUltrabithorax, abdominal-A is constant, but the results are not: hu- pioneering genetic studies of Edward and Abdominal-BÑis lethal. Yet such mans, mice, ßies and worms represent B. Lewis of the California Institute of mutant embryos survive long enough a wide range of body designs. Technology. Lewis has spent much of to develop specialized structures that Noting that variation, biologists have the past 40 years studying the bithorax indicate all eight abdominal segments often supposed that the molecular ar- complex, a small cluster of homeotic are replaced by thoracic segments. chitects of body formÑthe genetic pro- genes in the fruit ßy Drosophila mela- Most people would be unnerved by cesses that control embryonic develop- nogaster. The Greek word homeo means analogous birth defects in mammals, ment in diÝerent speciesÑwould also Òalike,Ó and the ßy homeotic genes are but these grotesque defects in ßies can be quite diverse. There is compelling so named because of their ability, when be observed with equanimity. evidence, however, that an interrelated mutated, to transform one body seg- group of genes, called HOM genes in ment of the fruit ßy into the likeness of rom his original genetic studies invertebrates and Hox genes in verte- another. Mutations in bithorax complex of the bithorax complex genes, brates, governs similar aspects of body genes usually cause such developmen- F Lewis derived two key insights. design in all animal embryos. tal defects in the posterior half of the The Þrst was that the normal function In at least some of the molecular sys- ßy body plan. Thomas C. Kaufman of of these homeotic genes is to assign Indiana University and his colleagues distinct spatial (or positional) identities have discovered and studied a second to cells in diÝerent regions along the cluster of ßy homeotic genes, the An- ßyÕs anterior-posterior axis. That is, C WILLIAM M GINNIS and MICHAEL tennapedia complex (named for the they ÒtellÓ cells that they are part of KUZIORA investigate the eÝects of the homeobox supergene family on animal founder gene of the complex, Antenna- the ßyÕs head or thorax or abdomen. development. McGinnis is professor of pedia). Mutations in these genes usual- These identities are to some extent ab- molecular biophysics and biochemistry, ly cause homeotic defects in the anteri- stract, in that the positional coordinates with an appointment in biology, at Yale or half of the ßy body plan. assigned by homeotic genes are inter- University. After earning his bachelorÕs It is often the case in biology that preted in dissimilar ways in diÝerent degree in biology from San Jose State bizarre defects in odd organisms con- developmental settings. Antennapedia University in 1978, he continued his tain the clues to solving important assigns thoracic identity during both studies in molecular biology at the Uni- versity of California, Berkeley. While problems, and few biological phenome- the embryonic and pupal stages of the working at the University of Basel dur- na are more bizarre than the disrup- ßyÕs life cycle, even though the struc- ing the mid-1980s, McGinnis and Mi- tions in body design caused by home- tures (sense organs, legs, wings and so chael Levine discovered the homeobox otic mutations. For example, some mu- on) that develop along the thorax diÝer sequence motif in genes of Drosophila tations in the Antennapedia gene can in larvae and adults. fruit flies. Kuziora has been assistant cause the antennae on the head of the LewisÕs second important insight was professor of biology at the University of fruit ßy to be transformed into an ex- that the linear order of the bithorax Pittsburgh since 1991. He received his tra pair of thoracic legs. Surprisingly, complex genes on the fruit ßyÕs chro- Ph.D. from the Baylor College of Medi- cine and worked with McGinnis for five some of the animals that develop the mosome exactly paralleled the order of years at Yale as a postdoctoral fellow. extra legs survive, feed and even mate the body regions they speciÞed along with normal ßies. the embryoÕs anterior-posterior axis. 58 SCIENTIFIC AMERICAN February 1994 Copyright 1994 Scientific American, Inc. ANTERIOR HEAD EMBRYOS of vertebrate animals as diverse as Þsh, sala- manders, birds, rabbits and humans show great similar- labial ities early in their development. Drosophila fruit ßies and other invertebrates develop along a very diÝerent path, yet at the earliest stages they and the vertebrates proboscipedia share a common pattern of expression of the so-called homeobox genes. That discovery reveals that despite the diÝerences in the Þnal appearance of the animals, Deformed they use closely related genes to specify parts of the body along the anterior-posterior (or head-tail) axis. Antennapedia Abdominal-B POSTERIOR TAIL DROSOPHILA FISH SALAMANDER CHICKEN RABBIT HUMAN SCIENTIFIC AMERICAN February 1994 59 Copyright 1994 Scientific American, Inc. dia mutations in adult ßies are caused by activity of Antennapedia in the head, where that gene is normally turned oÝ. In summary, the genetic evidence indi- cates that each HOM complex gene is needed to specify the developmental fate of cells in a certain position on the anterior-posterior axis: the posterior head, anterior thorax and so on. More important (and more instructive about their biological function), the activity of HOM complex genes is apparently suÛcient to determine the fate of at least some cells, even when those cells would not normally fall under a given geneÕs inßuence. he genes of the HOM complex are virtually the only ones in T Drosophila that have those prop- erties. They also share an interesting resemblance at the structural level be- cause all of them are members of the homeobox gene family. Homeoboxes are DNA sequences that carry the de- scriptions for making a related group of protein regions, all about 60Ðamino acid residues in size, called homeodo- mains. The homeo- preÞx in the name of these domains stems from their ini- tial discovery in Drosophila HOM pro- teins. Since then, however, homeodo- mains have been found in many other NORMAL FLY Antennapedia MUTANT FLY proteins with varying degrees of simi- larity. The homeodomains of the Dro- HOMEOTIC TRANSFORMATIONS, in which body parts develop in the wrong posi- sophila HOM proteins are especially tions, occur in fruit ßies that have mutations in their homeobox genes. Mutations similar to one another, which suggests of the Antennapedia gene, for example, can cause belts of thoracic denticles (spikes) to appear on the heads of larvae (top right). Another developmental con- they are closely related. For that rea- sequence of the mutation is that the mutant adults have legs growing in place of son, they are often referred to as An- antennae (bottom right). A normal larva and adult are shown at the left. tennapedia-class homeodomains. What do these HOM proteins do at the biochemical level? Only a super- The same relation also holds for the tivation overlap, but each HOM com- Þcial answer can be given at present. genes of the Antennapedia complex. plex gene has a unique anterior bound- They belong to a large group of pro- United by these shared characteristics, ary of activation in the body plan. teins whose function is to bind to DNA the genes in the bithorax and Antenna- If deletion of a gene or some similar in the regulatory elements of genes. pedia groupings are collectively re- incident interferes with the expression The right combination of these bound ferred to as the HOM complex. of a HOM protein, then embryonic cells proteins on a DNA regulatory element that normally contain high levels of will signal the activation or repression partial understanding of how the that protein often undergo a homeotic of a geneÑthat is, to start or stop mak- HOM complex genes determine transformation. That transformation ing that geneÕs encoded protein. Inves- A axial positions in the fruit-ßy occurs because of a backup HOM gene tigators have shown that the homeo- body plan can come from looking at that is already active in the same cells domain region of the HOM proteins is where those genes are active in em- and that can substitute its own posi- the part that directly interacts with the bryos. The HOM genes are present in tional information. For instance, if the DNA binding sites. the DNA of all of a ßyÕs cells but are ac- function of the Ultrabithorax gene is We are fascinated by the contrast be- tive only in some of them.
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