© 2001 by The Society for Integrative and Comparative Biology
The Role of Hox Genes in Axial Patterning in Hydra1
1 Department of Developmental and Cell Biology, University of California, Irvine, California 92697
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Hox genes in bilaterians specify distinct regions along the anterior-posterior axis. A question of interest is when in metazoan evolution did this class of genes take on this function. Hox genes have been isolated from a number of cnidarian species including hydra. The expression patterns of two of them, Cnox-3 and Cnox-2 have been examined in adult hydra. Cnox-3, a labial homologue, plays a role in oral/anterior patterning, while Cnox-2, a Deformed homologue or a Gsx homologue of the ParaHox cluster appears to repress anterior patterning in the body column. The two genes play a role in axial patterning that is consistent with the tissue dynamics of an adult hydra.
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INTRODUCTION |
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In general, a cnidarian polyp has a single oral-aboral body axis with radial symmetry. In most cnidarians little is known about the developmental processes involved in the generation of the body plan, and little is known about the genes involved in the mechanisms underlying these processes. Hox genes are known to play a major role in specifying regions along the anterior-posterior axis of the bilaterians. In recent years Hox genes have been isolated from a number of cnidarian species. (e.g., Schierwater et al., 1991
; Schummer et al., 1992; Shenk et al., 1993a; Kuhn et al., 1996; Finnerty and Martindale, 1997), Thus, it is of interest to examine the expression pattern of these Hox genes to determine if they play a role in axial patterning. Such information will also contribute to an understanding of when during metazoan evolution these genes first took on their roles in axis formation.
Several Hox genes have been isolated from hydra (Schummer et al., 1992; Shenk et al., 1993a). Given the tissue dynamics of an adult hydra as well the ability to manipulate the axial patterning processes in a number of ways, a reasonably detailed characterization of the function of genes can be carried out.
Tissue dynamics in hydra
In most animals axial patterning occurs during early stages of embryogenesis. The same is true for hydra, a freshwater cnidarian. However, these continue in an adult hydra because of the tissue dynamics of the animal. As shown in Figure 1, the body plan of an adult hydra consists of a single oral-aboral axis with radial symmetry. The head, body column and foot are the three regions along the axis. At a tissue level, an adult hydra is essentially a tube composed of two tissue layers, the ectoderm and the endoderm, which extend throughout the animal. A third cell lineage, composed of a multipotent stem cell, the interstitial cell and its differentiation products (neurons, nematocytes, secretory cells and gametes) reside among the epithelial cells (not shown in Fig. 1).
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The epithelial cells of the body column are continuously in the mitotic cycle dividing with an average cell cycle time of 72 hr (David and Campbell, 1972
). However, the adult animal is constant in size. Tissue of both layers of the body column is continually displaced towards the extremities (Campbell, 1967; Otto and Campbell, 1977). Thus, in the apical part of the body column, tissue is displaced up the body column, through the tentacle zone, and then out onto and along the tentacles (see Fig. 1). Eventually the tissue is sloughed at the tentacle tips. Similarly, tissue at the lower end of the column is displaced basally onto the foot and sloughed. However, most (75–85%) of the tissue is displaced onto developing buds, and when the buds have matured, they detach from the adult (Campbell, 1967). Thus, the adult is in a steady state of production and loss of cells, which accounts for the constant size of the animal. As there is no indication of aging in hydra (Martinez, 1998), this steady state goes on continuously.
Despite this continuous movement of tissue the morphology and the regional distribution of differentiated cell types remains constant (Bode et al., 1973). For this to occur, the processes governing axial patterning, morphogenesis and cell differentiation must also be constantly active. A pair of developmental gradients maintains the head at the apical end (e.g., MacWilliams, 1983a, b; for review see Bode and Bode, 1984) One is a gradient of head formation capacity, or head activation, while the other is a gradient of inhibition of head formation, or simply, head inhibition. Both are maximal in the head decreasing down the body column A second pair of similar gradients with maxima in the foot control foot formation (e.g., Cohen and MacWilliams, 1975). Because patterning processes are continuously active in the adult hydra, the genes involved these processes are expressed in the adult tissues as has been shown for a number of transcription factors known to be involved in axial patterning in hydra (Shenk et al., 1993a; Grens et al., 1996; Martinez et al., 1997; Gauchat et al., 1998; Broun et al., 1999; Technau and Bode, 1999; Smith et al., 1999).
Hox genes in hydra
Using PCR with either poly(A)+ RNA or genomic DNA fragments, we isolated five homeobox genes from hydra. Full length cDNA clones were isolated and sequenced for two of them, and their role in hydra characterized (Shenk et al., 1993a, b; Shenk et al., in preparation).
One of the two is Cnox-33, a homologue of labial, appears to play a role in specifying ectodermal tissue for tentacle formation (Shenk et al., 1993a; Shenk et al., in preparation). Tissue displaced up the body column invariably moves through the tentacle zone onto tentacles, but not into the hypostome (Campbell, 1967; Dübel et al., 1987). As tissue is displaced into the upper end of the body column there is evidence that it is specified to form tentacles (Hobmayer et al., 1990). Thereafter, as the sheet of cells moves across the tentacle zone/tentacle border (see Fig. 2 for structure of the head) the cells abruptly cease proliferation (Holstein et al., 1991), and begin differentiation. This sudden change is illustrated with TS19, an antibody that recognizes a surface antigen of the battery cells, the differentiated ectodermal cells of the tentacles (Bode et al., 1988). The antigen is not present on the epithelial cells on tentacle zone side of the border, but is present in a very high level in their immediate neighbors on the tentacle side of the border as well as all the ectodermal cells of the tentacles.
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The expression pattern of Cnox-3, as determined by in situ hybridization on whole mounts, follows these changes quite precisely (Shenk et al., in preparation). It is expressed at a high level in the upper end of the body column and in the tentacle zone, where tissue has been specified for tentacle formation (Fig. 3). However, expression stops abruptly at the tentacle zone/tentacle border suggesting expression ceases once differentiation begins. Cnox-3 is also weakly expressed in most of the body column, which is always presumptive head tissue. It is not expressed in the extremities where the cells are either differentiated or committed to a particular differentiation. In addition to the tentacles, these extremities include the hypostome, the lower peduncle, which is committed to foot formation, and the foot (see Fig. 1). Expression occurs only in the epithelial cells of the ectoderm. Hence, Cnox-3 expression coincides with specification of body column tissue for tentacle formation, and thus, the gene is most likely involved in this part of axial patterning.
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The other gene is Cnox-2, whose identity is a little less clear. As discussed below it may be a homologue of the Deformed/Hox-4 Hox gene, or of the Gsx class of ParaHox genes. As analyzed with an antibody against the Cnox-2 protein product, the gene is expressed in epithelial cells of both the ectoderm and endoderm. It is strongly expressed in the body column (Fig. 3) fading to a very low level in the upper eighth of the body column and the entire head (Shenk et al., 1993a
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As described in the following three examples, Cnox-2 expression drops dramatically whenever head formation occurs (Shenk et al., 1993b). [1] When an animal is bissected in the body column, the apical end of the lower half will regenerate a head. During that process, the high level of Cnox-2 expression at the apical end drops to the low level typical of the head, but remains high throughout the rest of this lower half. [2] Bud formation, hydra's asexual form of reproduction, begins with an evagination of the body column tissue about 2/3rds of the distance down the column from the head. The evagination develops into a cylindrical protrusion, and subsequently a head forms at the distal end and a foot at the proximal end. Thereafter, the bud detaches from the parent. During this process, Cnox-2 expression declines at the distal end shortly before tentacles begin to emerge indicating the formation of the head. [3] Finally, periodic treatment of an adult with diacylglycerol over the course of several days leads to the formation of ectopic tentacles and heads along the body column (Müller, 1989). With increasing time of treatment, and prior to the appearance of ectopic heads, the high level of Cnox-2 expression in the body column dropped to the low level observed in the head.
The high level of expression of Cnox-2 in the body column and foot coupled with low level of expression in the head, and the drop during head formation could be explained in one of two ways. The gene may specify epithelial cells as body column epithelial cells, or it could mean that Cnox-2 acts a negative regulator of head formation. There is some evidence for the latter idea.
ks1 is a gene that is expressed in the head region (Weinziger et al., 1994). An analysis of the promoter region of ks1 indicates the presence of a number of binding sites for transcription factors including several for Deformed (Endl et al., 1999). Isolation of nuclear proteins from the head and the body column revealed that those of the body column, but not those of the head bound to dfd-1, one of the Deformed binding sites (Endl et al., 1999). Since ks1 is not expressed in the body column, this result suggested that the nuclear proteins binding to this site were acting in a repressive manner. Interaction with an antibody against the Cnox-2 protein resulted in a supershift, as analyzed with gel electrophoresis, of one of the proteins binding to the dfd-1 site (Endl et al., 1999). This would indicate that one of the proteins binding to this binding site is the Cnox-2 protein, and thus, the protein acts as a negative regulator of a head-specific protein. Or, plausibly, it might be a negative regulator of head formation. The strong expression of the Cnox-2 protein in the foot as well as the body column is also more consistent with the idea that the gene has a role in repressing head formation instead of promoting body column formation.
One other aspect of the structure of the Cnox-2 gene is also consistent with its role as a repressor. Near its N-terminus, the Cnox-2 protein has a motif that could very well be the seven-residue eh1/GEH domain found in several classes of homeobox genes, and known to be involved in repression of transcription (e.g., Jimenez et al., 1999; Mailhos et al., 1999). Of the four residues (1,3,6,7) that are most conserved among the homeobox genes containing this domain, Cnox-2 shares two (1,3) of them (see Fig. 4) including the one (1) critical for the repression function (Tolkunova et al., 1998). The residues for the other two (6,7) are conserved substitutions.
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In sum, these two Hox genes appear to play a role in head formation in hydra. One, Cnox-3 is probably a positive regulator of head formation, or more precisely tentacle formation, while Cnox-2 may be involved in preventing head formation.
Relationship of Cnox-3 and Cnox-2 to axial patterning processes
Since both genes appear to have a role in the patterning of the head, are they involved in, or are their roles related to, the two gradients of head activation and head inhibition that govern head formation? The property of head activation provides tissue of the body column with the capacity to regenerate a head following bisection, or to form a head with a second axis upon transplantation to the body column of another animal. In the context of the continuous displacement of tissue in the body column, the head continuously produces a signal that is transmitted to the body column to maintain the head activation gradient in a steady state (MacWilliams, 1983b). As tissue is displaced up the body column, the level of head activation within the tissue continues to rise as the cells respond to an ever-increasing level of the graded signal that sets up the head activation gradient. One response to this rising level of head activation could be the expression of Cnox-3 when a threshold level of head activation is passed. This would begin the specification of the tissue for tentacle formation which is the eventual fate of all the apically-displaced body column tissue.
Since all the displaced tissue will end up in the tentacles, and none of it in the hypostome (Dübel et al., 1987), the question arises as to whether Cnox-3 expression is a response to head activation, considered to be a general head patterning process, or one specific for tentacle activation. More recent work on the behavior of several molecular markers during head formation in several contexts (Bode et al., 1988; Technau and Holstein, 1995; Mitgutsch et al., 1999; Smith et al., 2000), suggests that it is more appropriate to consider the patterning of the two parts of the head separately in terms of hypostome activation and tentacle activation. These ideas have been incorporated into a newer version of a reaction-diffusion model which explains a great deal of axial patterning in hydra very well (Meinhardt, 1993). Then, in these terms, a high level of Cnox-3 expression is a response to tentacle activation.
Because this high level of Cnox-3 expression is fairly constant throughout the upper eighth of the body column and tentacle zone, the expression appears to respond to a threshold level of tentacle activation. Were the level of expression a direct reflection of the level of tentacle activation, one would expect a graded distribution of Cnox-3 expression reflecting a gradient of tentacle activation. This was not observed (Shenk et al., in preparation).
The other gradient controlling head formation is the head inhibition gradient. The head continuously produces head inhibition and transmits it down the body column (e.g., MacWilliams, 1983a), most likely via gap junctions (Fraser et al., 1987) thereby preventing tissue of the body column from forming a head. The head inhibition signal is quite unstable with a half-life of 2–3 hr (MacWilliams, 1983a). Thus, when the head is removed, head inhibition rapidly decays, and the tissue of the body column can regenerate a head. The role of Cnox-2 may be linked to this gradient. It is expressed at a high level in the body column where head inhibition is active, and it represses a head-specific gene, and thus, may repress head formation. However, the connection between the two is not straightforward. Head inhibition is clearly graded down the column (e.g., MacWilliams, 1983b) while Cnox-2 expression is quite uniform, and extends into the foot.
Evolutionary considerations
In bilaterians, genes of both the Hox and Parahox clusters are expressed along the anterior-posterior axis (e.g., Brooke et al., 1998) In terms of the nucleotide sequence of their homeoboxes, the two hydra genes considered here both belong to the anterior class. Cnox-3, a homologue of labial/Hox-1 (Shenk et al., in preparation) is a member of the anterior class of Hox genes while Cnox-2, is part of the Gsx or anterior class of the ParaHox genes (Finnerty and Martindale, 1999). The expression pattern of Cnox-3 is also consistent with this designation. If the oral/aboral axis of hydra is assumed to be similar to the anterior/posterior axis of bilaterians, then Cnox-3 is expressed near the anterior end as are labial and its homologues in bilaterians. This suggests that the function of labial homologues in patterning of the anterior end of the anterior/posterior axis was established by the time cnidarians appeared in metazoan evolution.
Classifying Cnox-2 is a less clear. Originally, Cnox-2 was considered to be a homologue of Deformed/Hox-4 based on the sequence of the homeobox and of a domain at the N-terminal end of the protein (Shenk et al., 1993). This view is supported by the finding that the Cnox-2 protein binds to a Deformed binding site in the promoter of the head-specific gene, ks1 (Endl et al., 1999). Further, the Cnox-2 protein as does Deformed in the absence of Extradenticle acts as a repressor (Pinsonneault et al., 1997). With the more recent identification of the ParaHox genes, sequence comparisons of the same two regions indicates that Cnox-2 is more closely related to the Gsx class of ParaHox genes (Finnerty and Martindale, 1999). However, at first glance, the expression domain of Cnox-2 is not comparable to that of Gsx genes, as the latter genes where examined are expressed during the development of the brain (Szucsik et al., 1997) or the anterior gut (Li et al., 1996). In contrast, Cnox-2 is expressed in the body column and foot corresponding to trunk and posterior regions.
Depending on how one classifies the Cnox-2 gene, a couple of conclusions can be drawn. Assuming that Cnox-2 is a Hox gene, then there is a parallel in the pattern of expression between hydra and bilaterians. Labial is always expressed anterior to Deformed, while in hydra Cnox-3 is expressed anterior than is Cnox-2 (see Fig. 3). Thus, the sequence of expression of these two genes was established before the appearance of the bilaterians.
Assuming Cnox-2 is a ParaHox gene, and that the Hox and ParaHox clusters arose by duplication of an ancestral ProtoHox cluster, an interesting possibility arises. The ancestral anterior gene in the ProtoHox cluster may have given rise to both Cnox-2 and Cnox-3. One of them, Cnox-3, maintained the function of specifying the, or part of the, anterior region, while the other, Cnox-2, inverted its function into one of repression of the anterior region.
A final point concerns the evolution of the overall role of Hox (and ParaHox) genes. In bilaterians Hox genes play a role in specifying tissue for distinct regional fates along much of the length of the anterior-posterior axis. Once formed, all the regions along this axis are static and fully differentiated. In hydra the head and foot are fully differentiated, but the body column is not. Instead, it is in a dynamic state where the tissue is always capable of forming either head or foot, and the cells of the body column are not in an irreversibly differentiated state. Thus, hydra may have anterior and posterior regions, but no central or trunk region as defined in bilaterians. If so, the Hox (and ParaHox) genes may not have the same role in hydra as they do in bilaterians. Instead of each Hox gene defining a specific region along the anterior-posterior axis, their roles may be mixed. Some of them may define specific regions along the oral-aboral axis such Cnox-3 playing a role in anterior patterning, while others, such as Cnox-2, play an antagonistic role in preventing anterior patterning. This would be consistent with the fact that the two genes are expressed along most of the body axis.
It will be of interest to determine if any of the other Hox genes identified in hydra have roles in foot formation, and whether a similar antagonistic situation exists. It will also be of interest to learn to what extent these findings in hydra are applicable to other cnidarian species, especially the basal anthozoans. Do polyps of other cnidarian species have a tissue dynamics similar to that of hydra? And, what are the expression patterns of Hox/ParaHox genes along the body axis? In the one case for which data is available, the pattern of expression of Cnox-2 in the polyp of the colonial hydrozoan, hydractinia, is very similar to that of hydra: strong in the body column and weak in the head (Cartwright et al., 1999).
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ACKNOWLEDGMENTS |
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The work was supported by grants from the National Science Foundation (IBN-9723660 and IBN-9904757) and the National Institutes of Health (HD24511).
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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.
3 The gene referred to here and in Shenk et al. (1993a) as Cnox-3 is the same gene referred to as Cnox-1 in Schummer et al. (1992) and Gauchat et al. (2000).
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References |
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