Homology In Developmental Genetics: The Homeotic Genes
Introduction
Mutations in homeotic genes cause the replacement of one body structure by another normally located elsewhere (homoeosis: Bateson, 1894, pp. 84-85). Such body structures are usually serially homologous. Serial homology is a feature of metameric (segmented animals) where structures such as legs, nerve ganglia, spiracles, blood vessels, etc. occur in each segment. Thus the legs of a centipede are serial homologous to each other and to the mouthparts (mandibles, first and second maxillae) which have evolved from legs. Homeotic genes were first discovered in Drosophila—the Antennapedia complex and the Bithorax complex (ANT-C and BX-C) which control the anterior-posterior differentiation of the front half (head to second thoracic segment) and rear half (third thoracic segment to end of abdomen) of the body respectively (Lewis, 1963; Lewis, 1978; Kaufman, Lewis and Wakimoto, 1980) As examples of homeotic changes, a mutant of Antennapedia converts the Drosophila antenna to a thoracic leg; bithorax mutations convert the fly's halteres into a second pair of wings. Other examples are given by Raff and Kaufman (1983, chapter 8.)
These complexes of homeotic genes have two interesting features. One is that the physical order of the genes in a complex is identical to the order in which the genes are expressed along the anteroposterior axis of the embryo during development. The domains of expression along this axis correspond to the segments that are affected by mutations in these genes. Thus there is a colinear sequence between the genes on the chromosome and the structures along the anterior-posterior axis of the body that they affect (Graham, Papalopulu and Krumlauf, 1989.)
Secondly, it has recently been discovered that each gene in these complexes contains a highly conserved subsequence of 183 base pairs encoding for a DNA-binding domain of 61 amino acids called a homeobox (McGinnis, Levine, Hafen, Kuroiwa and Gehring, 1984; Riddihough, 1992a.) This finding proved to be a ‘rosetta stone' for finding pattern formation genes (Gehring, 1985; Maddox, 1984; Struhl, 1984; Slack, 1984.) Modern molecular genetics techniques could readily find genes containing the homeobox sequence and complexes of homeobox genes nearly identical to those found in Drosophila were subsequently found in a wide variety of animals including the mouse and the human! (McGinnis, Hart, Gehring and Ruddle, 1984; Levine Rubin and Tjian, 1984; Kessel and Gruss, 1990.)
Homeotic Genes In The Mouse
Vertebrates are metameric animals to a certain extent, their metameres including vertebrae, ribs, nerve cord ganglia, somatic muscle bundles, etc. The homeotic genes in the mouse, called Hox genes, perform the same function as those in Drosophila, i.e. controlling the anterior-posterior differentiation of the animal. The overlapping regions of expression of the various Hox genes along the anterior-posterior axis may form a code (Figure 1) that determines which target genes are to be activated (Gould, 1991; Riddihough, 1992b) The first metameric structures found to be controlled by these genes were the rhombomeres of the hind brain and associated branchial structures (Hunt et al, 1991; Simeone et al, 1992.)
The Surprising Degree Of Homology In Hox Complexes.
The fact that body plans as diverse as a fruit fly and a mouse should be determined by an almost identical underlying system of regulatory genes was an entirely unexpected discovery! Some vertebrate homeobox genes are structurally so similar to those in Drosophila that they can function in the fruitfly (Akam, 1989, 1991.) The mouse Hox-2.2 gene, virtually identical in its DNA sequence to the Drosophila Antennapedia (Antp) gene, induces transformations nearly identical to those of Antp, i.e. thoracic denticle belts in place of head structures and thoracic legs in place of antennae when introduced into Drosophila (Malicki, Schughart and McGinnis, 1990.) Similarly the human HOX-4.2 gene, structurally similar to the Drosophila Deformed (Dfd) gene can mimic the function of the latter in Drosophila (McGinnis, Kuziora and McGinnis, 1990; Malicki et al, 1992.) And the Deformed gene has the same effect in mice as the homologous mouse Hox gene (Awgulewitsch and Jacobs, 1992.)
The Homeotic Gene Complexes In Evolution
Comparative analysis indicates the subdivision of the Antennapedia-type homeobox genes into three classes early in metazoan evolution. Subsequent duplication generated a cluster of at least five genes in the common ancestor of insects and vertebrates eventually resulting in eleven of these genes in Drosophila (Schubert, Nieselt-Struwe and Gruss, 1993; Hoey, et al, 1986). Although the homeotic genes form two complexes in Drosophila, this is probably a peculiarity of dipterans. They exist in a single sequence (HOM-C) in other insects, such as the red flour beetle, Tribolium (Beeman, 1987; Stuart et al, 1991; Beeman et al, 1993.)
In vertebrates, tandem duplication, resulting in up to 13 linked genes, followed by duplication of these clusters occurred; each cluster later acquiring different secondary expression domains (Condie and Capecchi, 1994) allowing for the evolution of the more complex vertebrate body (Kappen, Schugart and Ruddle, 1989; Gaunt, 1991; Krumlauf, 1992; Holland, 1993; Pendleton, et al, 1993). Thus vertebrates, such as the mouse and human, have four Hox complexes. The corresponding genes in the complexes, identified by nucleotide sequence and their position in the Hox sequence, are paralogous and form a family. For example, Hox A3, B3 and D3 genes form a family (Figure 2.) There are 13 such families. Not all have members in all four complexes. The members of some families have identical function, while in other families the members have divergent functions.
The cephalochordate Amphioxus has only one complex. Amphioxus has only a small anterior swelling of the nerve cord, the cerebral vesicle, which passes for a brain (Garcia-Fernandez and Holland, 1994). Comparison of the anterior expression boundaries of mouse and amphioxus Hox genes suggests that the vertebrate brain is homologous to an extensive region of the amphioxus nerve cord containing the cerebral vesicle and extending posteriorly to somite four (Holland et al, 1992.)
Nomenclature Of Vertebrate Hox Genes
Initially the four vertebrate Hox clusters were designated 1-4 and the genes within each were assigned numbers in the order in which the genes were discovered. This system was unsatisfactory because it obscured the homologies between genes in the different clusters and between genes in different animals. In 1992 the nomenclature was revised. The four clusters were redesignated A-D and the genes within each cluster numbered according to their anterior-posterior sequence (Scott, 1992.) The new and old names for the genes are shown in Figure 2.
Hox Transformations In The Mouse:
In the past ten years, a great deal of research has elucidated the functioning of many of the 38 homeotic genes found in the mouse. Some of these results are summarized below:
- Hoxa-1: defects in hindbrain, associated cranial ganglia and nerves from rhombomere 3 to 8 including absence of rhombomere 5 (Carpenter et al, 1993; Mark et al, 1993); lack of 4th and 5th rhombomeres (Dolle et al, 1993); defects of brain rhombomeres 4 to 7: delayed hindbrain neural tube closure, absence of cranial nerves and ganglia, malformed inner ears and skull bones (Lufkin, et al, 1991); defects of external, middle and inner ears, hindbrain nuclei, cranial nerves and ganglia (Chisaka, Musci and Capecchi, 1992.)
- Hoxa-2: transformation of skeletal elements derived from second branchial arch in more anterior structures: duplication of Meckel's cartilage, ossification centers of the bones of middle ear (Gendron-Maguire et al, 1993); transformation of second to first branchial arch skeletal elements; includes atavistic reptilian pterygoquadrate (Rijli et al, 1993.)
- Hoxa-3: athymic, aparathyroid, reduced thyroid, other throat abnormalities, defects of heart and arteries (similar to human congenital disorder DiGeorge's syndrome) (Chisaka and Capecchi, 1991.)
- Hoxa-4: abnormal gut development as megacolon (Wolgemuth et al, 1989.)
- Hoxa-5: changes in cervical and thoracic regions including posterior transformation of the seventh cervical vertebra into the likeness of a thoracic vertebra complete with a pair of ribs (Jeanotte et al, 1993.)
- Hoxa.7: craniofacial anomalies: cleft palate, opened eyes at birth, nonfused pinnae (Balling, Mutter, Gruss and Kessel, 1989); malformations of basioccipital bone, the atlas and axis including an additional vertebra, a proatlas (Kessel, Balling and Gruss, 1990.)
- Hoxa-11: 13th thoracic segment transformed into additional 1st lumbar vertebra; sacral region anteriorized, forming another lumbar vertebra; changes in fore and hind limbs (Small and Potter, 1993.)
- Hoxb-4: transformation of second cervical vertebra from axis to atlas and defective sternum (Ramirez-Solis et al, 1993.)
- Hoxc-8: attachment of the 8th pair of ribs to sternum and appearance of a 14th pair of ribs on 1st lumbar vertebra (Le Mouellic, Lallemand and Brulet, 1992); extra ribs in lumbar region, transformation of the shape of posterior ribs into that of more anterior ones and joining of an additional pair of ribs to sternum (Jegalian and De Robertis, 1992.)
- Hoxd-3: anterior arch of atlas transformed to an extension of basioccipital bone of skull; axis shows atlas-like characteristics (Condie and Capecchi, 1993.)
Hox Genes And Vertebrate Limbs
The Hox A, C and D clusters are expressed in the limb buds. Those of the C cluster expressed in each limb (fore and hind) are different and are those expressed in the adjacent body mesoderm. Those of the A and D clusters are the same in each limb and are those expressed in the posterior body mesoderm (Figure 3.) In fishes and in the earliest tetrapods the pectoral and pelvic limbs are different in form. It has been suggested that early in the evolution of the tetrapods, the Hox A and D genes that controlled hind limb formation were co-opted for use in specifying pectoral fin pattern, resulting in the great similarity of the front and hind limbs in all later tetrapods (Tabin and Laufer, 1993; Coates et al, 1993.)
The Hox A and D genes appear to control the differentiation of the limbs along the anterior-posterior axis and partly along the proximal-distal axis (Dolle et al, 1989; Izpisua-Belmonte et al, 1991; Duboule, 1992; Morgan et al, 1992; Dolle et al, 1993.) There being only five distinct Hox-encoded domains across the limb bud, only five different types of digits can be formed, resulting in the basic pentadactyl limb. Although polydactyly, resulting in more than 5 digits is common, the extra digits are always duplicates of an adjacent digit (Tabin, 1992.)
Hox Genes And Feather Development In Birds
Homeobox genes are implicated in feather development in birds. Microgradients in Hox proteins occur within a single feather; macrogradients occur across feather tracts. Doses of retinoic acid, a suspected morphogen, cause transformations between feather and scale (Chuong, 1993). Retinoic Acid interferes with the normal establishment of Hox codes (Boncinelli et al, 1991; Kessel and Gruss, 1991; Marshall et al, 1994.)
The Role Of Hom-C Genes In Arthropod Evolution
Slight modifications of the homeotic genes in Drosophila can cause changes in the body organization mimicking the fruit fly's ancient ancestors. The absence of the bithorax gene produces the more primitive four-winged condition. The absence of the Antennapedia gene produces a thorax with three similar nonwing-bearing segments, mimicking the apterygote condition. If the entire BX-C sequence is missing, the posterior end of the embryo develops as a series of similar trunk segments reminiscent of trignathous myriapods. If both the ANT-C and BX-C complexes are missing, an embryo with three head segments and a series of trunk segments is produced resembling the onychophoran condition (Raff and Kaufman, 1983, p. 259.) Of course, only the pattern of segment identity has changed. The target genes controlled by the homeotic genes still produce Drosophila-like structures and, in fact, such mutant changes as described above are eventually lethal to the developing embryo.
The wing-bearing segments have two types of appendages: wings and legs. In the developing larva, the wing imaginal discs originate from the dorsal region of the leg discs. The primitive appendage of the arthropods was branched, the dorsal part forming a gill and the ventral part, the leg proper. This, along with paleontological evidence, suggests that wings evolved from the gills of primitive aquatic insects (Williams and Carroll, 1993.)
Homeobox Genes Found Throughout Living Kingdoms
Geneticists have searched everywhere for homeobox genes. They were found by McGinnis (1985) in Annelida (earthworm, leech), Arthropoda (shrimp, beetle, fly), Echinodermata (sea urchin), Urochordata (tunicate), Cephalochordata (Amphioxus), and Vertebrata (frog, chicken, mouse, human); by Holland and Hogan (1986) in Platyhelminthes (tapeworm), Brachiopoda, Nemertea, Mollusca (snail, sea hare), Echinodermata (starfish, sea urchin), and Chordate (mouse) and by Murtha, Leckman and Ruddle (1991) in mouse, fruit fly, swordtail fish, lamprey, ascidian, sea urchin, gastropod, hydrozoan, and hydroid. A homeobox gene has been found in the leech (Wysocka-Diller et al, 1989), in the nematode Caenorhabditis elegans (Kenyon and Wang, 1991; Cowing and Kenyon, 1992; Burglin et al, 1989) and the clawed frog, Xenopus (Carrasco et al, 1984.) The Knotted gene in maize was found to be a homeobox gene (Rennie, 1991) and homeo domains have been found in the alpha 1 and 2 mating type genes in yeast (Shepherd et al, 1984.)
Because of the ubiquity of homeotic clusters in animals, it has been suggested that the Hox system be adopted as the defining character of the kingdom Animalia and called the Zootype (Slack, Holland and Graham, 1993.) (The homeobox genes of plants, fungi and slime moulds do not fall in the homologous families of the genes comprising the zootype.) The extensive gene homologies in vertebrates and arthropods have prompted some authorities to revive the idea that a vertebrate is an upside-down version of an arthropod (Arendt and Nubler-Jung, 1994.)
Other Regulatory Genes
The homeotic genes we have been discussing are homeotic selector genes. In Drosophila there are other groups of pattern forming genes: the homeotic regulatory genes, which insure the correct spatial expression of the homeotic selector genes, and segmentation genes, which control the number and polarity of body segments in the fly (McGinnis, Garber, Wirz, Kuroiwa and Gehring, 1984.) In the mouse, apart from the Hox clusters, there are at least five other homeobox genes, corresponding to specific Drosophila genes; others containing not only a homeobox sequence but a second motif, the paired box (Pax) and still other homeobox genes contain a POU-specific domain (Kessel and Gruss, 1990.)
Certain of the Pax genes, which are also found in Drosophila and the squid Loligo, are involved in the development of the eyes of all these species. It is possible that eyes found in all animals may be partly homologous! (Quiring et al, 1994; Gould, 1994.)
Some Problems Solved
Changes in the Hox complex may be responsible for a variety of phenomena including: (1) the slight variations in rib numbers in fossil horses used as an argument against evolution by some creationists, (2) the shift in limb bud position in various vertebrates mentioned by de Beer, and (3) the partial homology of front and hind limbs. In the mouse, a Hox A11 mutant produces an enlarged sesamoid bone in both the fore and hind limbs (Small and Potter, 1993.) Is this the genetic basis for the panda's thumb?
Summary
The discovery of these all-pervading developmental genetic homologies underlying the diverse body plans of the animal phyla was an entirely unexpected phenomenon. Differences in body plans are partly due to differences in homeobox gene expression patterns and to the differences in the target genes regulated by them. The references cited below are only a fraction of the enormous literature on homeotic genes that has grown since 1984. See Gould (1991, 1994) and Ruddihough (1992b) for popular summaries of the homeobox genes.
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(from Frank Sonleitner's critique of Of Pandas and People)