The Evolution of Dorsoventral Pattern Formation in the Chordate Neural Tube1
SYNOPSIS. Living members of Phylum Chordata are divided into three groups: the Urochordata, the Cephalochordata (amphioxus) and the Craniata (vertebrates). These animals are united by a common body plan, a key component of which is the development of a neural tube dorsal to a notochord. Studying the genetics and embryology of these animals allows evolutionary comparison to be made between the mechanisms controlling the development of homologous body parts in different taxa. This paper focuses specifically on the evolution of dorsoventral pattern in the neural tube. In vertebrate embryos external inductive signals, originating from the notochord and the dorsal ectoderm, initiate a program of cell differentiation that subdivides the neural tube into a stereotyped pattern of neurons and glia. To understand the evolution of this pattern I have been characterising amphioxus members of the gene families involved, including genes from the HNF-3, Msx, Hh, Gli and Netrin families. Coupled with similar analyses of urochordate development, analysis of these genes shows that the signalling functions of the notochord and lateral ectoderm seem to predate vertebrate origins, and have not increased in complexity in vertebrates despite duplication of the gene families involved. Conversely, expansion of gene families downstream of these signals has increased the complexity of gene expression and function in vertebrate embryos. These data therefore provide an indication of how gene duplication and divergence may have provided the raw material for the evolution of the complex pattern of cell types that develops in the vertebrate neural tube.
Vertebrates share Phylum Chordata with two other living taxa, the Urochordata (ascidians and relatives) and the Cephalochordata (amphioxus), known collectively as the protochordates. These taxa are united by the possession of a rod-like mesodermal notochord and a dorsal, hollow neural tube, both key features of the chordate body plan. The neural tube of chordates develops from a sheet of ectoderm known as the neural plate. Typically the neural plate forms the neural tube by a "rolling up" process, although some chordates develop a neural tube exclusively by cavitation. The later, however, is considered a derived character. During the development of the vertebrate neural tube a precise pattern of cell differentiation is established. Along the dorsoventral axis this leads to the positioning of specific cell types in stereotypic locations and, while the pattern that develops shows some differences between different vertebrate taxa, a general underlying theme is apparent; for instance motor neurons develop in the ventral neural tube while sensory neurons and neural crest cells develop in the dorsal neural tube (Butler and Hodos, 1996).
The cellular and molecular mechanisms which control the development of this pattern have been the subject of intense scrutiny in recent years. In particular, tissues adjacent to the neural tube (the notochord to the ventral and the lateral ectoderm to the dorsal) have been implicated in the initial control of dorsoventral pattern. In all chordates the notochord lies ventral to the neural tube and expresses a number of transcription factor genes, including those of the HNF-3 class which encode fork head domain proteins (Lai et al., 1991; Dirksen and Jamrich, 1992; Ruiz i Altaba and Jessell, 1992). Notochord cells also express members of the hedgehog (Hh) family of cell signalling molecules, most importantly Sonic hedgehog (Shh) (Echelard et al., 1993; Krauss et al., 1993; Currie and Ingham, 1996). In amniotes, contact between hedgehog-secreting cells of the notochord and naive neurectoderm leads to the induction of a specific cell population known as the floor plate at the ventral midline of the neural plate (Placzek et al., 1993; Echelard et al., 1993; Roelink et al., 1994, 1995). Floor plate cells activate expression of both HNF-3 and Shh and can also be recognised by the expression of other markers, such as F-spondin and Netrin (Klar et al., 1992; Kennedy et al., 1994). Throughout subsequent development floor plate cells retain a characteristic non-neuronal morphology and have a critical role in axon guidance.
The induction of dorsal cell types occurs in an analogous manner. Dorsal signals initially derive from adjacent lateral ectoderm and are mediated by members of the Tgf(beta) family, particularly those of the Bmp2/4 and Bmp-5/6/7/8 types (Liem et al., 1995; Takahashi et al., 1996). In the chick embryo at least one member of each type (Bmp-4 and Bmp-7) are expressed in the lateral ectoderm and studies have suggested that Bmp-2/4 and Bmp-5/6/7/8 molecules may hetero- as well as homodimerise (Liem et al., 1995; Lyons et al., 1995). Bmp signalling from the ectoderm induces the expression of multiple Bmp genes in the dorsal neural tube, in conjunction with the expression of other markers such as transcription factors of the Msx and snail families (Liem et al., 1995; Shimeld et al., 1996; Takahashi et al., 1996). At the cellular level this results in the development of dorsal cell types such as sensory neurons and neural crest in the dorsal neural tube.
Neural tube cells are therefore subject to two sources of external inductive signals, Hh and Bmps. This polarises the neural tube by the induction of expression of the same signalling molecules by dorsal and ventral neural tube cells. Other neural cells then seem to interpret relative proximity to these two signals by activating expression of particular genes. This results in the partitioning of the neural tube into defined areas of gene expression, with members of many gene families involved in the control of development expressed in particular subsets of cells (Ekker et al., 1992; Gruss and Walther, 1992; Nieto et al., 1994; Tsuchida et al., 1994; Appel et al., 1995; Mayor et al., 1995; Thisse et aL, 1995; Shimeld et al., 1996). The spatial localisation of some of these genes, including members of the Msx, snail, Pax3/7, Pax4/6, HNF-3 and LIM-homeodomain families, is shown schematically in Figure 1. These gene families all encode transcription factors and current models suggest that the restricted expression of such genes directly influences the region-specific differentiation of cell types, an hypothesis supported by genetic evidence (Pfaff et al., 1996). Additional interactions between different cell types are then likely to further refine this pattern (Pfaff et al., 1996). Thus in amniotes a picture is emerging of the cellular and molecular mechanisms that control cell pattern along the dorsoventral axis of the neural tube. In anamniotes the expression of many of these genes has also been studied and typically conforms with that of amniotes (Ekker et al., 1992; Appel et al., 1995; Mayor et al., 1995; Thisse et al., 1995), although there is some evidence that differences may exist in the cellular mechanisms which lead to the establishment of these patterns of gene expression (Shih and Fraser, 1996).
The similarity between all vertebrates studied to date suggests these patterning mechanisms at least predate the origin of teleosts and, given the similar pattern of cell types that develops in elasmobranch, lamprey and hagfish embryos, probably predate the origin of living vertebrates (Butler and Hodos, 1996). This raises the question of how far back in evolution can these mechanisms be traced? The closest living relatives of the vertebrates are amphioxus and the urochordates: Most phylogenies place amphioxus as the sister group of the vertebrates, with urochordates more distantly related (Turbeville et al., 1994; Wada and Satoh, 1994). The ascidians (the best studied urochordates) have a simple neural tube which for the majority of its length consists of a few ependymal cells and no neurons, although this may have degenerated from a more complex nervous system (Crowther and Whittaker, 1992; Wada et al., 1996). In contrast the amphioxus neural tube develops a pattern of cell types that in some respects is similar to that seen in vertebrates; only motor neurons develop in the ventral neural tube while sensory neurons, exiting via a mixed dorsal root, are present in the dorsal neural tube (Bone, 1960). There is also histological evidence for a floor plate at the ventral midline (Lacalli et al., 1994). However, despite this similarity to the basic vertebrate pattern, the amphioxus neural tube is much simpler than that of vertebrates. The total number of cells is small and some cell types are apparently absent, including the neural crest, the evolution of which many authors consider a key event in the evolution of vertebrates (Gans and Northcutt, 1983). Coupled with this apparent anatomical simplicity is a genetic simplicity. Vertebrate evolution has been accompanied by large scale gene duplications, probably by tetraploidy, resulting in families of closely related genes (Lundin, 1993; Sharman and Holland, 1996). Amphioxus seems to have split from the vertebrate lineage prior to these duplications; thus many gene families which have multiple members in vertebrates are represented by fewer and often one member in amphioxus (Garcia-- Fernandez and Holland, 1994; Holland et al., 1994). One persuasive hypothesis suggests that the gene duplications which occurred after the separation of the vertebrate lineage from that of amphioxus provided the genetic "raw material" necessary for the evolution of new morphological features (Holland and Garcia-Fernandez, 1996).
To understand how vertebrates have evolved new morphological features and patterns of cell differentiation we must address the underlying genetic and developmental changes that have occurred during vertebrate evolution. By analysis of developmental genes in protochordates ancestral patterning mechanisms can be identified, allowing the deduction of developmental genetic innovations specific to vertebrates. The application of such analysis to dorsoventral pattern formation in the neural tube has progressed rapidly, with members of the Msx, snail, Dlx, Pax, HNF-3, Bmp and Hh gene families isolated from a variety of protochordates. Detailed analysis of these genes is starting to reveal both conserved ancestral and vertebrate-specific features of neural patterning.
RESULTS AND DISCUSSION
Protochordate genes from gene families involved in the dorsoventral patterning of the vertebrate neural tube are listed in Table
1. The majority of these are transcription factors and many are expressed in protochordate embryos in patterns that shed light on the evolution of the chordate neural tube.
Ventral signals in amphioxus and ascidians
Both amphioxus and ascidians develop a mesodermal notochord ventral to an ectodermal neural plate. The notochords of all chordates have long been considered homologous on a developmental and positional basis (Hatschek, 1881; Willey, 1894). Molecular evidence also supports this homology; the notochords of all chordates studied express the transcription factors HNF-3 and Brachyury (Holland et al., 1995; Corbo et al., 1997; Olsen and Jeffery, 1997; Shimeld, 1997; Terazawa and Satoh, 1997). One of the first markers for floor plate induction in vertebrates is the activation of HNF-3 expression in those cells of the ventral neural tube which are in direct contact with the notochord. Previous reports have suggested that both amphioxus and ascidians also express HNF-3 genes in the ventral neural tube (Fig. 2) (Corbo et al., 1997; Olsen and Jeffery, 1997; Shimeld, 1997). How is this expression activated? In amphioxus, an Hh homologue (AmphiHh) is also expressed in the notochord at a time consistent with activation of HNF-3 in the neural tube (unpublished observations, S.M.S.). Furthermore ventral midline cells of the amphioxus neural tube also activate expression of AmphiHh and a third marker of floor plate cells, Amphi-- Netrin (unpublished observations, S.M.S.) (Fig. 2). These data strongly suggest that the first stages of ventral signalling, the induction of a specific group of cells at the ventral midline of the neural tube, are conserved between amphioxus and vertebrates. The activation by amphioxus floor plate cells of both AmphiHh and AmphiNetrin also suggests that two of the functions of the floor plate in vertebrate development, the patterning the ventral neural tube and axon guidance, are also conserved between amphioxus and vertebrates.
Dorsal signals in amphioxus and ascidians
In vertebrates, dorsal pattern is induced by members of the Bmp family of cell signalling proteins (Liem et al., 1995; Takahashi et al., 1996). The diversity and pattern of expression of Bmp genes in amphioxus is unreported, however in the ascidian Halocynthia roretzi both a Bmp-2/4 homologue (HrBMPb) and a Bmp-5/6/7/8 homologue (HrBMPa) are expressed in ectoderm cells adjacent to the neural plate (Fig. 2B) (Miya et al., 1996, 1997). This suggests that dorsal signals, including the potential for heterodimerisation between different Bmp types, may also be conserved between protochordates and vertebrates, although this does not lead to induction of HrBMPa or HrBMPb expression in the dorsal neural tube of ascidians, as in vertebrates. It is impossible to determine if this is a derived or ancestral feature, especially considering the likely degenerate nature of the ascidian neural tube. Analysis of Bmps in amphioxus may be more informative in this respect.
Subdividing the neural tube: Responses to dorsal and ventral signals
The evidence described above shows that the neural tube of protochordates is probably exposed to the same dorsalising and ventralising signals as the vertebrate neural tube, and that these signals issue from homologous tissues. Analysis of the hedgehog signalling pathway in Drosophila and vertebrates has identified the members of the Gli family of zinc finger transcription factors as a key part of the signal transduction pathway that receives the hedgehog signal. In vertebrates, Gli genes are expressed in the neural tube in both gene- and species-- specific patterns, for instance in Xenopus laevis Gli-1 is expressed early in the midline but later around the midline, while Gli2 and Gli-3 are expressed throughout the neural plate but excluded from the midline (Lee et al., 1997). In mouse embryos Gli1, -2 and -3 show slightly different patterns of expression compared to their Xenopus orthologues, however on summing their expression patterns a consistent picture emerges: Vertebrate Gli expression encompasses the whole neural plate early in development but later is down regulated in the midline (Lee et al., 1997). An amphioxus Gli homologue, AmphiGli, is initially expressed throughout the neural plate and subsequently down regulated in the midline (unpublished data, S.M.S.). The conserved nature of Gli genes as receivers of Hh signalling suggest that all neural plate cell are capable of responding to Hh signalling in both amphioxus and vertebrates.
Exposure of the vertebrate neural tube to dorsal signals results in the induction of Msx and snail expression in dorsal cells (Liem et al., 1995; Shimeld et al., 1996). Induction of Msx expression by Bmp signalling is a common feature of vertebrate development and in mouse embryos leads to overlapping but distinct patterns of Msx1, -2 and -3 in the dorsal neural tube (Graham et al., 1993; Vanio et al., 1993; Liem et al., 1995; Shimeld et al., 1996): In amphioxus an Msx homologue (AmphiMsx) is also expressed in the neural tube, however expression is not restricted exclusively to dorsal cells but extends ventrally to the floor plate (S.M.S., A. Sharman, and P.W.H. Holland, unpublished observations) (Fig. 2C). In ascidians three genes from families considered dorsal in vertebrates have been characterised. An Msx homologue from Molgula oculata is expressed in the neural plate, although its sequence seems unusually divergent (Ma et al., 1996). In Halocynthia roretzi the Pax-3/7 homologue HrPax-37 is expressed in the dorsal-most cells of the neural tube, similar to the expression of vertebrate Pax-3/7 (Wada et al., 1996). However, the Ciona intestinalis snail homologue Ci-sna is expressed in the lateral cells of the neural tube and not restricted to the most dorsal cells, as in vertebrates (Corbo et al., 1997). Therefore, neither dorsal ascidian genes or dorsal amphioxus genes show complete conservation of expression with their vertebrate homologues. Such differences in gene expression should perhaps be expected between taxa with such morphologically different neural tubes, and may be informative in constructing the evolutionary history of neural tube patterning. In this regard two basic hypotheses can be invoked: The first is that the pattern of gene expression seen in basal chordates is ancestral. This would imply that the differences in this pattern seen in vertebrates reflect their evolution of a more complex dorsoventral polarity in the neural tube; an example of this might be the insertion of a novel domain of cells that do not express either Msx or HNF-3 between the ancestral domains of HNF-3 and Msx, which in amphioxus abut. The second hypothesis suggests that the differences are due to changes specific to the amphioxus or ascidian neural tubes, and therefore that the ancestral chordate had more complex dorsoventral polarity. An example of this is the expression of Ci-sna and HrPax-37 in ascidians, where the expression of these genes in the dorsal three cells of a four cell neural tube may reflect the degeneracy of the ascidian neural tube rather than an ancestral condition. These hypotheses are not mutually exclusive since it is possible that ascidians may show derived expression due to degeneracy while amphioxus shows ancestral expression (or indeed vice versa). The difference between them is one of evolutionary polarity (that is the direction of change), and cannot be resolved with current data, although the examination in one protochordate group of genes already characterised in the other would help. Additionally, an examination of lower chordate phylogeny, as recently established by ribosomal RNA sequence, has indicated taxa that would further clarify this question (B. J. Swalla, personal communication; Wada, 1998). These analyses show the ascidians are a paraphyletic assemblage of derived urochordates, and that the most basal living urochordates are a group called the appendicularians. Appendicularians develop a neural tube that is morphologically more complicated than that of ascidians. Molecular phylogeny has also shown hemichordates, a Phylum which also develops a dorsal, tubular nervous system, to be an outgroup to the chordates. The development of neither hemichordates nor appendicularians has been studied at the level of neural patterning and such an analysis would probably reveal the polarity of the differences described above, illuminating the basic molecular changes that underlie the morphological differences of vertebrate, amphioxus and ascidian neural tubes.
Gene duplication and the evolution of dorsoventral patterning in vertebrates
In amphioxus, the Hh, Gli and Msx families are all probably represented by single genes (my unpublished observations). While there are two HNF-3 genes in amphioxus, these demonstrably arose from a duplication specific to the amphioxus lineage and therefore the common ancestor of amphioxus and vertebrates only had one HNF-3 gene (Shimeld, 1997). In vertebrates, all these gene families have multiple members. What role did the expansion of these gene families during vertebrate evolution play in the evolution of dorsoventral pattering? In the case of the Hh genes, it would seem relatively little. In amniotes only Shh is expressed in the notochord and floor plate, and mutation of this gene abolishes ventral signalling (Chiang et al., 1996). Thus expansion of the Hh family has probably not resulted in added complexity to ventral signalling, either by the notochord or the floor plate, in ancestral vertebrates, although in zebrafish a more recent duplication may have (Ekker et al., 1995). Dorsally in the chick, only Bmp-4 and Bmp7 are expressed at the right time and place. It would thus seem that this initial signal has also not changed, despite gene duplication, since only one member of each family need be present. In contrast, dorsal neural tube cells exposed to Bmp signalling activate expression of a wider range of Bmp genes, suggesting increased complexity has evolved at this step of the patterning process (Liem et al., 1995, 1997). Similarly, the Gli and Msx families, potential targets or interpreters of the signals, have different but overlapping patterns of expression in the neural tube and, in the case of the Gli proteins, have also diverged biochemically (Catron et al., 1996; Ruiz i Altaba, 1997). This shows increased complexity downstream of the signals, with changes at at least two levels; divergence by differential regulation of duplicated genes at the transcription level plus functional divergence as characterised by different transcriptional activation capabilities. Taken together, these data show how gene duplication and divergence has increased the complexity of vertebrate neural tube patterning compared to protochordates.
CONCLUSIONS AND PROSPECTS
The characterisation of developmental genes in protochordates is shedding light on the developmental genetic changes which have accompanied, and perhaps driven, vertebrate evolution. From the data gathered to date it would seem as if the early stages in dorsal and ventral signalling have been relatively static during the evolution of vertebrates. Rather, complexity has increased downstream of these signals, with gene duplication and divergence playing a central role. The next and more challenging step will be to determine how genetic changes such as the modification of expression patterns have occurred, and to determine the effect of these and of gene duplications on development. In this way we will begin to understand how changes in developmental genes may have lead, via ontogeny, to the evolution of new morphological features and a more complicated body.
1From the Symposium Developmental and Evolutionary Perspectives on Major Transformations in Body Organization presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 3-7 January 1998, at Boston, Massachusetts.
2 E-mail: email@example.com
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Corresponding Editor: Gregory A. Wray
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Division of Zoology, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, P.O. Box 228, Reading RG6 6AJ UK
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