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ScienceWeek
EVOLUTIONARY BIOLOGY: ON THE CLUSTERING OF HOX GENES
The following points are made by Nipam H. Patel (Nature 2004 431:28):
1) Some of the most striking discoveries in developmental biology over the past century concern the set of genes called homeotic (Hox) genes. Genetic studies in fruitflies first showed that these genes have a major role in producing the head-to-tail (anterior-posterior) pattern of tissues along the body axis. Then came the startling finding that the order of these genes along a chromosome correlates with the anterior-posterior position of the body regions they control, and with the domains in which the genes are expressed. It soon became apparent that the same relationship exists in other animal groups, including vertebrates. However, it seems that somewhere in the evolutionary lineage leading to the tunicate Oikopleura dioica, the Hox complex has disintegrated(1)
2) Evolutionary analyses have suggested that the common ancestor of bilaterally symmetrical creatures -- which include most animals, the main exceptions being cnidarians and sponges --probably possessed at least seven Hox genes, organized into a single complex. Within the lineage leading to vertebrates, gene duplications led to an expansion of the cluster, and then the cluster itself underwent duplications, leading to the four copies of the Hox complex now found in humans and mice. All along, the collinearity of the genes -- the correspondence between their physical order along chromosomes and their domains of expression and function -- was maintained.
3) But why has collinearity been preserved? The ancestral bilaterian complex itself probably arose through several rounds of local duplications, explaining how the genes first became organized as a cluster. In general, however, gene order is constantly shuffled by chromosomal rearrangements such as inversions and movements of large DNA segments. Given the rate at which this process occurs, the maintenance of collinear organization over at least 600 million years of evolution must not just be due to chance(2). One possibility is that different Hox genes once shared, and continue to share, regulatory elements. But although this idea might account for the preservation of some degree of organization, it seems inadequate to explain the extent to which the complex has been maintained. Another possibility is that the mechanism that allows the genes to be expressed in a strict anterior-posterior expression pattern requires some type of higher-level organization, involving the progressive chemical or structural modification of a large contiguous stretch of DNA.
4) The work of Duboule et al(3) over the past few years has added an extra dimension to the issue of collinearity. They have shown that the vertebrate Hox genes demonstrate not just spatial but also temporal collinearity; that is, genes at one end of the complex are expressed not only in the anterior of the embryo, but also relatively early in development. Hox genes located further along the complex are expressed both more posteriorly and later. Duboule et al(4) have provided evidence that it may be the requirement to maintain temporal collinearity that is responsible for keeping the complex together. A Hox gene experimentally moved around within the complex can retain spatial information, but will have an altered temporal expression profile.
5) Continuing this theme, Seo et al(1) provide an example of an animal in which the Hox complex has not stayed together yet appears to maintain some degree of ordered spatial expression along the anterior-posterior axis. Their studies focus on Oikopleura dioica. Oikopleura is a type of tunicate, but is quite distant from Ciona, the other well-studied representative of this group of animals. Tunicates are evolutionarily primitive relatives of vertebrates, and comparisons between living tunicates and vertebrates may help researchers to piece together the features of the common invertebrate ancestor that gave rise to vertebrates. Oikopleura also has a remarkable genome -- it is very small (at 60-70 megabases) and compact (with one gene every 4 kilobases)(5).
References:
1. Seo, H. -C. et al. Nature 431, 67-71 (2004)
2. Patel, N. H. & Prince, V. E. Genome Biol. 1, reviews1027 (2000)
3. Kmita, M. & Duboule, D. Science 301, 331-333 (2003)
4. van der Hoeven, F., Zakany, J. & Duboule, D. Cell 85, 1025-1035 (1996)
5. Seo, H. -C. et al. Science 294, 2506 (2001)
Nature http://www.nature.com/nature
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Related Material:
DEVELOPMENTAL BIOLOGY: HOX PROTEINS AND BODY PATTERNING
The following points are made by M. Kmita and D. Duboule (Science 2003 301:331):
1) In the course of animal embryogenesis, distinct morphological identities are established along the body axes. For example, mammals have thoracic vertebrae that bear ribs, whereas cervical vertebrae do not, and digits are eventually positioned at the distal ends of our limbs, rather than elsewhere. The genetic mechanism underlying this patterning system was uncovered by studying mutations in the fruit fly Drosophila melanogaster in experiments in which correct structures were wrongly positioned. Drastic alterations, such as the outgrowth of a limb instead of an antenna or of a wing in place of a haltere, are associated with the misexpression of gene members of the Hox family of transcription factors.
2) Because HOX proteins are at work in animals displaying a variety of morphologies, they likely act as developmental switches, rather than as specific stonework of the body architecture. Twenty-five years ago, Lewis showed that Hox genes were clustered along the chromosome, colinear with their domains of action in the thorax and abdomen of flies. This observation was subsequently extended to vertebrates and other animals, leading to the suggestion that morphological diversity along the body axis was generated by a combinatorial distribution of HOX products (the "HOX code"). How do such proteins differentially instruct cohorts of cells about their fates, and how are their functional domains established in time and space?
3) In flies, 8 Hox genes belong to the Antennapedia and Bithorax clusters (the "HOM complex"). In many instances, these proteins act by regulating a few downstream effectors sufficient to trigger alternative developmental pathways, with the discriminative help of various cofactors. By these means, an embryonic field can be specified as a whole, such as the limb imaginal disc, where suppression of the Distalless limb-promoting function by the Hox genes Ubx and abdA prevents the appearance of limbs in the abdomen. This suppression does not occur in the thorax despite the expression of Antp. HOX proteins can also affect the determination of a particular cell fate during oenocyte differentiation and during head formation.
4) In summary: During vertebrate development, clustered genes from the Hox family of transcription factors are activated in a precise temporal and spatial sequence that follows their chromosomal order (the "Hox clock"). Recent advances in the knowledge of the underlying mechanisms reveal that the embryo uses a variety of strategies to implement this colinear process, depending on both the type and the evolutionary history of axial structures. The search for a universal mechanism has likely hampered our understanding of this enigmatic phenomenon, which may be caused by various and unrelated regulatory processes, as long as the final distribution of proteins (the HOX code) is preserved.
Science http://www.sciencemag.org
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Related Material:
ON BODY PATTERNING IN DEVELOPMENT
The following points are made by Y. Takahashi et al (Proc. Nat. Acad. Sci. 2001 98:12338):
1) Ontogenesis (the developmental processes of an individual animal) begins with a fertilized egg, and through proliferation, this single cell becomes a homogeneous mass of cells. This mass of cells then becomes subdivided into distinct groups that eventually will exhibit functional specialization later in development. If the units fail to be correctly established in time and space, certain specializations might be entirely missing from the embryo, or cells might randomly differentiate (specialize) in the wrong place. Furthermore, cells specializing in the wrong place may end up dying because they fail to be properly integrated with the rest of the organism. All of these outcomes can have dire effects on the body.
2) The progress of organogenesis is governed by patterning processes that have occurred earlier during development and that involve the action of cell-cell signaling pathways, growth factors acting between cells, and transcription factors acting within cells. In general, both body segmentation and brain patterning are essential for conferring a highly organized functional complexity to the body. In both cases, an originally homogeneous group of cells obtains characteristics to give rise to particular structures and functions in a precise spatial and temporal pattern. This produces patterns such as the regular repetition of skeletal elements and the 3-dimensional compartments of brain primordium on which the subsequent complexity of the neuronal network is organized. It is now widely accepted that similar sets of factors are shared by different animal species and also by distinct processes in the course of early patterning of organogenesis. During animal evolution, a "prepattern" of fundamental organs apparently emerged relatively early.
Proc. Nat. Acad. Sci. http://www.pnas.org
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