© 2001 by The Society for Integrative and Comparative Biology
Cnidarians Reveal Intermediate Stages in the Evolution of Hox Clusters and Axial Complexity1
1 Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215
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Across major phylogenetic comparisons, the evolution of Hox clusters generally parallels the evolution of axial complexity. Sponges lack a fixed primary body axis and regional axial differentiation. Correspondingly, sponges appear to lack a Hox cluster. Bilaterian animals are characterized, at least primitively, by the presence of an anterior-posterior axis. In many bilaterians, the anterior-posterior axis is finely subdivided into morphologically distinct regions; e.g., consider the many distinct vertebrae of the human vertebral column or the many distinct body segments of the fruitfly. This axial complexity is encoded in part, by the genes of the Hox cluster. Bilaterians possess from seven to upwards of forty Hox genes which sort into four monophyletic classes (anterior, group-3, central, and posterior). Cnidarians (e.g., sea anemones) display an intermediate stage of axial complexity. Unlike sponges, they possess a fixed primary body axis, known as the oral-aboral axis, with a distinct head, body column, and foot. However, the primary axis of cnidarians lacks the degree of axial differentiation found in vertebrates or insects. Cnidarians possess distinct anterior and posterior Hox genes. Cnidarians appear to lack group-3 or central Hox genes. Southern mapping experiments in the sea anemone, Nematostella indicate linkage between an anterior Hox gene, an even-skipped ortholog, and a posterior Hox gene. The linkage of eve to a Hox gene, a condition previously described in a coral, is found in vertebrates but apparently absent in insects. Cnidarians hold the potential to reveal important intermediate stages in the evolution of Hox clusters and axial complexity.
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INTRODUCTION |
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Two major discoveries fueled the current interest in Hox evolution. (1) Mutations in Hox genes can produce profound morphological change. (2) Hox genes are phylogenetically widespread among metazoans and therefore represent an evolutionarily ancient component of metazoan developmental regulatory systems. These two discoveries suggest that the evolution of Hox genes may be causally related to the evolution of animal body plans. However, recent evidence suggests that the nature of the link between Hox genes and morphology may vary greatly depending on the phylogenetic context.
For example, in the early days of comparative Hox studies, an appealingly simple and intuitive hypothesis about the link between Hox genes and morphology was put forward. Perhaps the complexity of an organism along its anterior-posterior body axis is proportionate to the number of Hox genes it possesses (Akam et al., 1988
; Kappen et al., 1989). Clearly, this relationship does not hold for certain clades. Within the Ecdysozoa, a superphyletic assemblage comprising arthropods, nematodes, and their relatives, certain lineages have evolved much greater axial complexity than the ecdysozoan ancestor, without having evolved additional Hox genes (reviewed in Finnerty and Martindale, 1998). Simply put, within the Ecdysozoa, axial complexity varies enormously, while the number of Hox genes is nearly constant. In segmented Ecysozoa, axial complexity can be equated with the number of morphologically distinct body segments or appendages. For example, the Onychophora possess 20 or so pairs of identical walking legs. In contrast, arthropods such as the lobster possess distinct maxillipeds, pereopods, pleopods, and uropod (Pechenik, 2000). While the axial complexity of arthropods can greatly exceed that of onychophorans, the complement of Hox genes appears to be the same in these two phyla (Grenier et al., 1997). This is not to say that Hox genes have not been involved in the evolution of axial complexity in ecdysozoans. Modifications in the spatiotemporal expression patterns and the "interactional architecture" (Arthur, 1997) of Hox genes have contributed to major changes in body plan within this clade (e.g., Averof and Patel, 1997; Carroll et al., 1995; Castelli-Gair and Akam, 1995; Weatherbee et al., 1998).
Changes in gene expression and genetic interactions will not be the topic of this review, however. Rather, I will focus on major changes in Hox gene number during evolution. The bilaterian ancestor inherited a fairly complete Hox cluster comprising perhaps eight hox genes representing all four of the present day Hox classes (anterior, group 3, central, and posterior; reviewed in Finnerty and Martindale, 1998). Therefore, the study of present-day bilaterians cannot inform us about the origin and initial elaboration of Hox gene complexes.
Our ability to make inferences about the evolution of complex molecular characters, such as Hox clusters, can be greatly assisted by the survival of lineages possessing intermediate character states. To our benefit, lineages demonstrating important intermediate stages of Hox evolution have survived to the present day, particularly among the non-bilaterian animals. Data from sponges, ctenophores, and cnidarians are providing a glimpse into the some of the earliest events in Hox evolution. In this paper, I will review the accumulating Hox data from cnidarians (Table 1), and discuss its possible signficance for Hox evolution and morphological evolution. Major differences exist between the Hox complements of cnidarians and bilaterians, and between the Hox complements of cnidarians and sponges. Such differences represent quantum leaps in developmental potential, which may have had profound consequences for morphological evolution.
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Cnidarians in Metazoan phylogeny and evolution
The phylum Cnidaria comprises approximately 10,000 species of tentacle bearing aquatic animals. Two major adult body types characterize the phylum: the medusa is typically a mobile pelagic organism, and the polyp is typically a sessile benthic organism. The four classes of extant Cnidarians vary with respect to the possession of the polyp and medusa (Fig. 1). The Anthozoa (sea anemones and corals) possess only the polyp form. The trachyline Hydrozoans possess only the medusoid form. Other cnidarians, including the Scypohozoa (true jellyfish), Cubozoa (sea wasps or box jellyfish) and most hydrozoans (Hydra and its relatives) can alternate between the polyp and medusa in the course of a complete life cycle. Hydra itself has secondarily lost the medusa stage. In the alternating "metagenic" lifecycle, the polyp generally reproduces asexually by fission or budding, while the medusa reproduces sexually. The Anthozoa are considered the basal member of the phylum, and the polyp-only lifecycle is believed to represent the primitive condition for cnidarians (Bridge et al., 1995
; Odorico and Miller, 1997; Fig. 1). Anthozoan polyps reproduce both sexually and asexually.
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Cnidarians occupy a pivotal postion in metazoan phylogeny. They are an outgroup to bilaterians, but they share a common ancestor with the Bilateria to the exclusion of the sponges (Fig. 1). Cnidarians may be informative about body plan evolution in the metazoa both because of what they share with bilaterians and what they lack. For example, cnidarians resemble bilaterians in the possession of several key evolutionary innovations that are lacking in sponges such as tissue-level organization, nerve cells, and muscle cells. However, cnidarians lack certain bilaterian innovations such as a through-gut and a dorsal-ventral axis (reviewed in Nielsen, 1995
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Hox-like genes in cnidarians
In 1991, Murtha and coworkers applied degenerate PCR to the recovery of homeobox fragments from a wide range of taxa, including the cnidarians Sarsia and Hydractinia (Murtha et al., 1991
). Since that time, the degenerate PCR approach, supplemented by ligation-mediated PCR, RACE, and library screening, has resulted in the recovery of dozens of Hox-like genes from 11 species of Cnidaria (Table 1).
Individual Hox-like genes from cnidarians have been assigned various identities, depending on the criteria used for assessing homology and the breadth of bilaterian genes included in the comparison. An instructive example is the cnox2 gene of hydrozoans, also referred to as anthox2 when isolated from anthozoans, and scox2 when isolated from a scyphozoan. Cnox2 is the best studied of the cnidarian Hox-like genes. Homeodomain sequences for this gene are available from eight species (Table 1), full-length cDNAs have been isolated from three species (Nematostella, Finnerty and Martindale, 1999; Chlorohydra, Schummer et al., 1992; Hydractinia, Buss and Cartwright, unpublished data), and its expression has been studied in two species (Schummer et al., 1992; Shenk et al., 1993). Homeodomain alignments with bilaterian Hox genes suggested homology to the Drosophila gene Deformed, a central-class Hox gene (Schummer et al., 1992). Initial phylogenetic analyses failed to assign cnox2 to a specific class of Hox genes (Finnerty, 1998; Finnerty and Martindale, 1997; Schierwater and Kuhn, 1998; Schierwater et al., 1991). Subsequently, a more inclusive phylogenetic analysis of Hox and ParaHox genes identified cnox2 as an ortholog of the anterior ParaHox gene GSX (Finnerty and Martindale, 1999). This example illustrates the importance of making the appropriate evolutionary comparisons. When assigning orthology to Hox-like genes, phylogenetic analysis should include at a minimum Hox genes, ParaHox genes, and an appropriate outgroup.
The term ParaHox was coined by Brooke and coworkers when they identified a compact cluster of three Hox-like genes in the genome of the cephalochordate, Branchiostoma. The ParaHox cluster of Branchiostoma spans approximately 33 kilobases and contains the genes GSX, XLOX, and CDX. These genes resemble Hox genes in that (1) they are clustered, (2) they have Hox-like homeodomains, (3) they are expressed in restricted domains along the anterior-posterior axis, and (4) they appear to obey the property of spatial colinearity (i.e., the genes are expressed along the anterior-posterior axis in an order that parallels their order in the ParaHox cluster). Phylogenetic analysis of homeodomain sequences indicates that GSX groups with anterior Hox genes, XLOX groups with group-3 Hox genes, and CDX groups with posterior Hox genes. Brooke and coworkers hypothesized that the Hox cluster and ParaHox cluster had resulted from the duplication of an ancestral ProtoHox cluster, most likely in the common ancestor of bilaterian animals. Therefore, each of the ParaHox genes is most closely related to a particular class of Hox genes.
Individually, ParaHox genes have been reported from a wide range of bilaterian animals including vertebrates, arthropods, and annelids. Likewise, ParaHox genes appear to be clustered in vertebrates (Coulier et al., 2000; Pollard and Holland, 2000). The clustering of ParaHox genes helps us to recognize the close evolutionary relationship between specific Hox genes and specific ParaHox genes. These recently recognized evolutionary relationships, in turn, have broad consequences. Hox genes can no longer be regarded as an exclusive (i.e., monophyletic) gene family whose evolution can be studied in isolation from the other Hox-like genes. Additionally, ParaHox genes become an evolutionary marker for Hox genes, and vice versa. If these two clusters trace their ancestry to a single event, a cluster duplication, then any lineage possessing a descendant of the original ParaHox cluster must derive from a lineage that also possessed the original Hox cluster (Finnerty and Martindale, 1999).
As indicated during the discussion of cnox2, the ParaHox hypothesis has already had an impact on the interpretation of cnidarian Hox-like genes. Whether cnidarians possess true Hox genes (e.g., Finnerty and Martindale, 1997; Martinez et al., 1998), or simply Hox-like genes (e.g., Holland, 1998) is a question of considerable importance for interpreting the evolution of axial properties in the Metazoa (Holland, 1999). The evolutionary scenario proposed by Brooke and co-workers establishes a Hox timeline which allows us to state this question more precisely (Fig. 3). Depending on the relative timing of Hox evolution and lineage splitting, cnidarian Hox-like genes might represent direct descendants of the ancestral Hox cluster (Hox genes), direct descendants of the ProtoHox cluster (ProtoHox genes), or perhaps direct descendants of the original preProtoHox gene (Finnerty and Martindale, 1999). Each possibility generates a distinct phylogenetic prediction (Fig. 3).
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A recent phylogenetic analysis, including Hox-like genes from the sea anemone, Nematostella and both Hox and ParaHox genes from the cephalochordate, Branchiostoma, clearly supports the conclusion that cnidarians possess distinct Hox genes and ParaHox genes (Finnerty and Martindale, 1999
). Genes from the anemone group with individual classes of Hox genes or ParaHox genes from Branchiostoma, indicating that the original cluster duplication must have preceded the evolutionary split between these two lineages (Fig. 4). Specifically, anthox6, anthox7, and anthox8 group with the anterior Hox genes of Branshiostoma, anthox2 groups with the anterior paraHox gene GSX, anthox1 groups with the posterior Hox genes, and anthox4 groups with the posterior ParaHox gene CDX. In addition to strong resemblance within the homeodomain (Fig. 2), anthox2 displays strong sequence similarity with the GSX gene family outside of the homeodomain (Finnerty and Martindale, 1999).
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Phlylogenetic analyses of homeodomain sequences are limited by the amount of data available for comparison (60 amino acids). Additional evidence for Hox evolution can be gained from genomic organization. Genomic organization is highly conserved among Hox clusters, though the Hox clusters of the fruitflies Drosophila melanogaster and Drosophila virilis, and the nematode, C. elegans have undergone major genomic rearrangements (reviewed in Finnerty and Martindale, 1998
). Southern mapping experiments on the sea anemone, Nematostella vectensis, indicate linkage between an anterior Hox gene, anthox6, an even-skipped ortholog, anth-eve, and a posterior Hox gene, anthox1 (Fig. 5). Linkage of an orthologous anterior Hox gene (antpC) and an even-skipped gene (eveC) is also known from the coral Acropora (Miller and Miles, 1993). Lambda clones spanning the genomic region containing anthox6 and anth-eve have been isolated and partially sequenced (Finnerty and Martindale, unpublished data). Partial sequencing of these clones, in combination with low stringency Southern hybridizations using homeobox probes, has failed to identify additional Hox genes within this genomic segment. At this time, we must consider the possibility that cnidarians lack the central class and the group 3 Hox genes.
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In two key respects, the Hox linkage pattern of Cnidaria resembles vertebrates more than insects. First, the genes are relatively tightly spaced (<10 kilobases). In insects, the distance between neighboring hox genes is on the order of 70–100 kilobases (Beeman, 1987
; Ferrier and Akam, 1996; Lewis, 1978). In vertebrates, the distance between neighboring Hox genes is on the order of 7–10 kilobases (for example, Graham et al., 1989). The Hox genes of the cephalochordate Branchiostoma are spaced about 30 kilobases apart (Garcia-Fernandez and Holland, 1996). Several lines of evidence suggest that this difference between Hox cluster organization in insects and vertebrates is likely to have functional and evolutionary consequences. For example, while several instances of enhancer-sharing between neighboring hox genes have been demonstrated in vertebrates, the promoters of adjacent hox loci in insects appear to be insulated from each other (reviewed in Mann, 1997).
The linkage of even-skipped to a Hox gene is the second important similarity between cnidarians and vertebrates. In both the sea anemone Nematostella (Fig. 5; Finnerty and Martindale, unpublished data) and the coral Acropora (Miller and Miles, 1993), even-skipped is closely linked to a Hox gene. Close physical proximity to the Hox cluster is argued to have important regulatory consequences for even-skipped homologs in vertebrates (Dollé, 1994). In the mouse, there are two eve genes, Evx1 and Evx2. Evx2 is closely linked to the Hoxd13 gene (8 kilobases distant). Evx1 is more distantly linked to the Hoxa13 gene (45 kilobases distant). Evx2 is expressed in spatial and temporal sequence with the genes of the nearby Hox cluster. Its is expressed further posterior and later than the neighboring gene Hoxd13, as if it were operating under the principle of colinearity. Evx1 expression does not obey Hox colinearity (Duboule, 1994; Dollé, 1994).
The Hox and ParaHox data from cnidarians suggest new interpretations of Hox evolution. One possible scenario is depicted in Figure 6. The original Hox and ParaHox clusters predated the split between Cnidaria and Bilateria (Finnerty and Martindale, 2000). These original clusters consisted of three members: an ancestral anterior gene, a group 3 gene, and a posterior gene. The anterior Hox class may have expanded to two members prior to the divergence of Cnidaria and Bilateria (Hox1/anthox6 and Hox2/anthox7; Finnerty, 1998; Finnerty and Martindale, 1997, 1999). The central Hox class originated in the bilaterians subsequent to the divergence of bilaterians from cnidarians, perhaps by an unequal crossing-over event between two of the existing Hox genes (Gehring et al., 1994; Kmita-Cunisse et al., 1998). In other words, the homeobox region of central class Hox genes may be derived partly from a posterior homeobox and partly from an anterior or group 3 homeobox. Group 3 genes may have been lost in the Cnidaria. No new ParaHox genes appear to have evolved since the origin of the cluster in the eumetazoan ancestor.
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Axial properties of cnidarians, bilaterians, and sponges
There are major qualitative differences between the primary body axes of sponges, cnidarians, and bilaterians. Sponges grow by accretion and therefore lack a fixed primary axis (Kaandorp, 1991, 1994
). In contrast to sponges, cnidarians and bilaterians have a fixed primary axis (Nielsen, 1995) which displays the property of terminal axial delimitation (Finnerty, 1998). The relative relationship among structures along the primary axis is preserved during growth of the animal (Fig. 7).
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The primary axes of cnidarians and bilaterians are referred to in different terms. The cnidarian primary body axis is the oral-aboral axis, while the bilaterian axis is the anterior-posterior axis. However, it is possible that the oral-aboral axis of cnidarians and the anterior-posterior axis of bilaterians are homologous at some level. Nielsen has proposed direct structural homology of the oral-aboral axis of Cnidaria and the anterior-posterior axis of Bilateria on the basis of conserved larval features. In the Cnidaria and many indirect developing Bilateria, the adult body axis develops along the larval apicobasal axis, which passes through the apical tuft (Nielsen, 1995
). Even in the absence of direct structural homology, there might be homology in the developmental mechanisms responsible for axial patterning.
A hypothetical scenario for the evolution of axial patterning which assumes homologous axial patterning mechanisms is presented in Figure 8. In this scenario, terminal axial delimitation evolves in the common ancestor of the eumetazoa from a sponge-like ancestor with no fixed primary body axis. Once the axis is delimited, it undergoes extensive subdivision, particularly in the bilaterian ancestor. Extant cnidarians inherit a primary body axis that is delimited, but not extensively subdivided, reminiscent of the ancestral eumetazoan. In this scenario, the acquisition of terminal delimitation, or a fixed body axis, is homologous in eumetazoans, and would be underlain, at least initially, by homologous developmental mechanisms (Finnerty, 1998; Nielsen, 1995).
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This scenario for axial evolution has clear parallels with the Hox evolution scenario depicted in Figure 6. The initial evolution of Hox and ParaHox clusters, with anterior and posterior classes, would precede or coincide with the evolution of terminal delimitation. The further elaboration of the Hox cluster, including the origin of the central class Hox genes, would precede or coincide with the extensive axial subdivision which has occurred in the bilaterian radiation. The data are not yet available to fully assess the role of Hox genes in axial patterning of cnidarians, but considering the pervasive and conserved role of Hox genes in axial patterning among bilaterians, it appears likely that Hox genes were involved at earlier stages of axial evolution. The only way to address this hypothesis is by studying the Cnidaria, and possibly other non-bilaterian taxa that may reveal intermediate stages.
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ACKNOWLEDGMENTS |
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The author is indebted to Mark Q. Martindale of Kewalo Marine Lab PBRC/University of Hawaii for constructive comments on this manuscript and overall superb mentoring. This research was supported by National Science Foundation #9727244 grant to M.Q.M. and J.R.F.
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FOOTNOTES |
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1 From the Symposium HOX Clusters and the Evolution of Morphology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2000, at Atlanta, Georgia.
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