Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria

“Genes of the HOX CLUSTER are integrated into animal axial differentiation, and are even present in CNIDARIANS , such as coral”

“…adhesion and transcription factor genes are widely conserved across Metazoa including morphologically simple taxa such as cnidarians and sponges (Finnerty and Martindale 1999; Kusserow et al. 2005; Miller et al. 2005; Technau et al. 2005; Nichols et al. 2006; Ryan et al. 2006; Adamska et al.…”

“Recently, two groups have independently published analyses that strongly support the idea that cnidarians diverged after the ProtoHox stage of evolutio”

“These studies consistently reported the existence of anterior (hox1 and/or hox2 related) and posterior (hox9–14 related) homeodomains in the Cnidaria [44,46,48,63,64,75].”

“According to the neighbor-joining tree, the HOX2 family may also be represented in Nematostella, which would be consistent with previously published homeodomain phylogenies that have identified putative anterior Hox genes (HOX1 and HOX2 families) in the Cnidaria [17,38,39,51].”

“…from bilaterians: they lack a two-ended gut; they lack bilateral anterior– posterior body plans; they lack any Hox genes of the “middle” class (Finnerty and Martindale, 1999; de Rosa et al., 1999; Yanze et al., 2001); they lack central nervous systems; and perhaps most importantly, they…”

“These genes are closely related to Hox genes, suggesting this ‘ParaHox’ gene cluster is an ancient paralogue (sister) of the Hox gene cluster [5,16,17].”

“, 1998)) probably existed in the last common ancestor of cnidarians and bilaterians (Finnerty and Martindale, 1999; Kourakis and Martindale, 2000; Schierwater and Desalle, 2001).”

“The bootstrap values for any particular grouping of Hox vs ParaHox genes range from 40 to 70% (Brooke et al, 1998; Finnerty and Martindale, 1999; Banerjee-Basu and Baxevanis, 2001; Minguillón and Garcia-Fernàndez, 2003).”

“The results confirm several key aspects of previously published studies [7, 13, 18, 24] but do not support others.”

“Other aspects are more controversial and there are conflicting views concerning the early history of the Hox/ParaHox genes (e.g. [31,69,73,78]).”

“These events most probably precede the divergence of the lineages leading to cnidarians and to triploblast bilaterians (Finnerty and Martindale 1999; Ferrier and Holland 2002), thus focusing attention on more basal lineages of metazoan life.”

“, 1998) andParaHox genes (Finnerty, 1998; Finnerty and Martindale, 1999), the genomic linkage of a Hox gene to an even-skipped ortholog (Finnerty, 2001), and the expression of Hox genes in a manner colinear to their genomic organization (Finnerty and Martindale, in preparation).”

“Clear orthologues are present for anterior (PG1) and posterior (PGs 9–13) Hox genes (Finnerty and Martindale 1999; Gauchat et al. 2000; Ferrier and Holland 2001).”

“The structural relationship between the cnidarian genes and the Hox/ParaHox genes from bilaterians raises interesting questions about their function in the patterning of the body axis in basic phyla ( Finnerty and Martindale, 1999; Kuhn et al., 1999; Martinez et al., 1998; reviewed in Galliot, 2000).”

“…to laboratory manipulation has already made it a productive system for exploring cnidarian development and the origins of bilateral symmetry (Finnerty and Martindale 1999; Finnerty et al. 2004; Fritzenwanker et al. 2004; Kusserow et al. 2005; Magie et al. 2005; Matus et al. 2006; Torras and…”

“Remarkably, GSX is also statistically the best supported group and the only one for which sequence conservation extends outside from the homeodomain [61].”

“Furthermore, Hox and ParaHox genes are now known to have originated before the evolution of crown cnidarians (Finnerty and Martindale 1999) and are inferred to have been present in clusters, implying that the “modern” patterning apparatus was in place long before the origin of the early bilaterians in which set-aside…”

“Strong support for orthology of cnox2 with gsx is consistent with recent phylogenetic analyses (Finnerty and Martindale 1999; Gauchat et al. 2000; Hayward et al. 2001).”

“The only promising lead has been the previously mentioned link between a Hox-like gene and an even-skipped-like gene, first reported in Acropora (Miller and Miles, 1993) and since confirmed in another anthozoan, Nematostella (Finnerty and Martindale, 1999).”

“vectensis is extensively investigated as model organism for embryonic development [23,24] and recent sequencing of its genome revealed a surprisingly high similarity to the human genome [25].”

“Hox HDs, only a limited phylogenetic analysis was undertaken (Fig. 1D), as a number of phylogenetic studies of cnidarian Hox-like sequences have recently been published ( Finnerty and Martindale 1999; Kuhn et al. 1999; Gauchat et al. 2000).”

“…understanding of anthozoan development while illuminating critical events in the early evolution of animals such as the origin of bilateral symmetry (Finnerty et al. 2004), anterior–posterior patterning (Finnerty & Martindale 1999), and triploblasty (Scholz & Technau 2003; Martindale et al. 2004).”

“Recent studies have shown that homologues of many regulatory genes acting in the development of the Bilateria are also present in cnidarians (Finnerty and Martindale, 1999; Gauchat et al., 2000; Yates, 2000), some of them also occurring in sponges, the basal-most living metazoans (Adell et al.,…”

“Cathepsin is a protease that functions in phagolysosomes to aid in the destruction of phagocytosed pathogens and is broadly expressed in pigment cells, glia, and undetermined mesenchymal cells in planaria.(40,84,85) Additionally, cathepsin is considered an important modulator during wound healing by the degradation of…”

“On the other hand, the typical Hox genes with their 3′–5′collinear arrangement that are characteristic for trunk formation in higher organisms have not been found in Hydra”

“In another example, the use of homologous genes to achieve bilateral symmetry in larvae of sea anemones was used to infer that bilaterality originated before the split of Cnidaria and Bilateria [82] (Fig.”

“Hox genes are well characterised in cnidarians and, given their importance in embryonic development, it is not surprising that molecular evidence from the Cnidaria reveal that the genetic origins of Hox genes predate the cnidarian-bilaterian divergence [83-85] yet had evolved after divergence of the sponge and eumetaz…”

“The clustering of the Antennapedia superclass of homeobox genes in contemporary genomes is proposed to be the outcome of tandem gene duplication and cluster duplications from an ancestral UrArcheHox gene during metazoan evolution [2,3].”

“This hypothesis is readily tested given recent studies on Hox genes and their function in cnidarian and more basal diploblastic animals (Martinez et al., ’98; Schierwater and Kuhn, ’98; Finnerty and Martindale, ’99).”

“…genes) implies the genesis, by tandem duplication, of the central Hox gene in the Hox cluster, after the duplication of the ProtoHox cluster (Finnerty and Martindale, 1999; Ferrier and Holland, 2001); the 2-gene cluster model (one anterior, one posterior) implies the genesis, after the…”

“…analysis and Southern blotting provided evidence for the existence of a Hox cluster in N. vectensis (Finnerty 2001), and the presence of both Hox and ParaHox genes (Finnerty and Martindale 1999) further supports the hypothesis that the Hox cluster originated before the emergence of cnidarians.”

“Accordingly, the genome encodes many proteins known to be involved in appendage development of arthropods and vertebrates, including a Hox gene cluster (Finnerty and Martindale, 1999; Chourrout et al., 2006), Fibroblast growth factors (FGFs) (Matus et al.”

“This gene, along with the Trichoplax gene Trox-2, has been proposed to be either a gsx parahox homolog (Finnerty and Martindale, 1999; Finnerty et al., 2003) or a protohox gene belonging to the Diplox-2 gene family, which also contains the Trichoplax gene Trox-2 (Schierwater and Kuhn, 1998; Jakob et al.”

“0 DTD and Martindale determined that pregnancy does not increase the risk of hemorrhage (21).”

“Holland [10] suggested that this function has been lost for Gsh because the position of the mouth has changed in this branch of the Bilateria.”

“The picture has been complicated by the discovery of the ParaHox sister group (Brooke et al., 1998) and the finding that cnidarians, diploblasts with only rudimentary (or vestigial) symmetry, possess both Hox and ParaHox genes (Finnerty & Martindale, 1999).”

“For instance, the idea that the origin of the Hox cluster of homeobox-containing developmental control genes directly triggered the diversification of bilaterian animals is not supported, as the Hox cluster predates the appearance of most metazoan body plans by a substantial interval [25].”

“The A-3-P three-gene model is based on evolutionary parsimony (Finnerty and Martindale, 1999; Ferrier and Holland, 2001a): The apparent absence of central ParaHox genes in bilaterians and cnidarians, coupled with the lack of central Hox genes in cnidarians, suggested a simpler, three-gene composition of the original P…”

“Within cnidarians, this method has been primarily used in the model systems Hydra and Nematostella vectensis (Finnerty and Martindale, 1999; Kurz et al., 1991; Wolenski et al., 2013a,b).”

“The three ParaHox gene families, Gsx (or Gsh or ind), Xlox (or Xlhbox8, IPF1, PDX1, IDX1, STF1 or Lox3) and Cdx (or caudal/cad) are widespread within Bilateria (Ferrier and Holland, 2001a) and at the origin of chordates the ParaHox genes were linked in a tight cluster with Xlox located between Gsx and Cdx (Brooke et a…”

“Thus, they are considered evolutionary sister (or paralogue) clusters [1-7].”

“Gsx genes have been reported to be closer to Hox Anterior group genes, Xlox to PG3 genes, and Cdx to Hox Posterior genes [13,25-27].”

“Phylogenetic evidence suggests that Hox and ParaHox cluster are sister clusters, both being descendants from an ancestral ProtoHox cluster (Brooke et al., 1998; Finnerty and Martindale, 1999).”

“Up to five Hox genes have been found in a single cnidarian (Finnerty and Martindale, 1999; Kuhn et al., 1996, 1999).”

“, 2004 [56,45,17]”

“2), anthox2 displays strong sequence similarity with the GSX gene family outside of the homeodomain (Finnerty and Martindale, 1999).”

“ParaHox genes have been identified both in cnidarian species and in all major branches of bilaterians (Brooke et al., 1998; Finnerty and Martindale, 1999; Frobius and Seaver, 2006; Hui et al., 2009; Ryan et al., 2007), and their products play conserved roles in the regulation of tissue patterning and differentiation d…”

“Cnox-2 has been classified as an ortholog of the ParaHox gene GSX (Finnerty and Martindale, 1999).”

“The emergence of Nematostella vectensis as a model system began with the developmental and field studies of Hand and Uhlinger in the early 1990s (16–18), and it gained momentum with the publication of the first molecular studies (19, 20 ), which demonstrated that the starlet sea anemone could yield key insights into e…”

“References for the several eh1/GEH domains are Xgsc: Blumberg et al., 1991; Dgsc: Goriely et al., 1996; Cngsc: Broun et al., 1999; en (DM): Poole et al., 1985; en (Ce): Wilson et al., 1994; NK2: Kim and Nirenberg, 1989; CnNK2: Grens et al., 1996; Cnox-2; Shenk et al., 1993a; Anthox2: Finnerty and Martindale, 1999; Gsh…”

“Second, observations from the recently sequenced cnidarian Nematostella vectensis suggest that the Cnidaria may contain only two groups of Hox and ParaHox genes, which has led to the suggestion that the ProtoHox cluster may have contained either two or three genes, rather than four (Finnerty and Martindale, 1999; Ferr…”

“In fact, they have both Hox genes, which in bilaterians regulate colinear development of ectoderm or neuroectoderm, and ParaHox genes, which are similarly expressed in structures derived from endoderm (Brooke et al, 1998; Finnerty and Martindale, 1999; Gauchat et al, 2000; Kourakis and Martindale, 2000).”

“Thus, there appear to be two distinct anterior Hox groupings in the Cnidaria, as has been suggested previously (Finnerty, 1998; Finnerty and Martindale, 1997; Finnerty and Martindale, 1999; Kourakis and Martindale, 2000), but one of the groupings may be anthozoanspecific (see Ppox4 group in Fig.”

“Magie C, Daly M, Martindale MQ. 2007.”

“As Hox genes are known in Radiata (but not in choanoflagellates or sponges), they were presumably present in the last common ancestor of Radiata and Bilateria (see, for example, Finnerty & Martindale 1999).”