© 2001 by The Society for Integrative and Comparative Biology
Hox Genes and Axial Specification in Vertebrates1
1 Wesleyan University, Biology Department, Middletown, Connecticut 06459
2 University of North Carolina, Department of Biology, Chapel Hill, North Carolina 27599
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The colinear, anterior to posterior expression domains of the Hox genes in vertebrate embryos is strongly correlated with regional changes in vertebral morphology. The limbs of tetrapods are consistently aligned with specific areas of the vertebral column. However, control of limb development is apparently situated in the lateral plate mesoderm, and has been experimentally shown to be independent of an axial Hox code (Cohn et al., 1997
, Nature 387:97–101). We have used experimental manipulation of chick embryos to test the causal role of Hox genes in patterning derivatives of the paraxial mesoderm. Hox expression in heterotopically transplanted segmental plate responds in a manner consistent with a patterning role for these genes in the morphological behavior of the transplants. Expression is maintained in dorsal paraxial regions where patterning is also intrinsic to the donor site of the graft. However, expression is apparently lost in somite cells that migrate into the host lateral plate environment and form appropriate host-level muscles. This arrangement could enable increased plasticity in the evolution of transpositional variation in the vertebrate body plan. |
INTRODUCTION |
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SYNOPSISINTRODUCTIONRESULTS AND DISCUSSIONReferences |
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Experimental embryology provides a means for exploring the intrinsic mechanisms that underlie morphological evolution. This paper will discuss experimental results that explore the evolutionary significance of Hox gene expression in the patterning of the anterior-posterior (AP) axis in vertebrates. The detailed experiments are reported elsewhere (Nowicki and Burke, 2000
). This paper will focus on a discussion of their relevance to understanding the role developmental mechanisms play in generating axial pattern, and how those mechanisms may act as nodal points in the evolution of morphology.
The vertebrate musculoskeletal system is formed from two populations of embryonic mesoderm (Fig. 1). The post-cranial axial skeleton arises from somites, as do virtually all of the striated muscles of the body. The somatic layer of the lateral plate gives rise to the appendicular skeleton and the connective tissue of the limbs and body wall. Changes in the arrangement and proportions of these basic anatomical elements account for much of the morphological variation that has appeared during the course of vertebrate evolution. A common form of variation among vertebrates is described by the term "transposition," coined by E. S. Goodrich at the beginning of the last century (Goodrich, 1906, 1913). Transposition describes differences in the numbers of segments, or somites, contributing to different regions of the body in different animals. The axial formula of an animal is the number of segments included in each anatomical region (Fig. 1a). A change in somite number in an axial region produces a transpositional change in the axial formula.
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The somites are serially homologous embryonic structures. Each somite along the anterior-posterior (AP) axis shares a pattern of early developmental changes identical to every other somite (Fig. 1b). Furthermore, each somite contains cells that contribute to muscle, bone, and dermis. Many local factors that determine cell differentiation within the somite have been identified (reviewed in Hirsinger et al., 2000). The ultimate pattern that the somite cells participate in, however, is dramatically different depending on the AP position of the somite. This global patterning requires the coordination of somite fate with regard to all the other somites along the axis, as well as in the context of lateral tissue. The information responsible for global patterning is less well understood (Burke, 2000
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Developmental mechanisms act to generate and constrain evolutionary change
The basic body plan of vertebrates is quite conservative despite transpositional variation in the axial formulae of different species. In tetrapods, the limbs are consistently aligned with specific axial levels. Regardless of variation in the number of segments in each region, the forelimb always lies at the cervical to thoracic transition, and the hindlimb at the lumbosacral transition (Fig. 1a). The embryonic limb buds form in lateral plate tissue. Thus, to allow proper arrangement of the appendicular skeleton with regard to the axial skeleton, patterning information in the lateral plate mesoderm must be aligned with that in the somites. To account for this consistency through transpositional evolutionary changes, both intrinsic and extrinsic factors can be evoked. Functional constraints on locomotion could produce strong selection against decoupling limb placement from the axial formula in tetrapods (many fish taxa do not appear to share this constraint). This selection would also act at the level of the developmental mechanisms leading to intrinsic constraints of the patterning system that would make such a decoupling highly unlikely.
The patterning mechanisms used to control morphogenesis are principal targets for evolutionary changes that lead to novel morphologies. Given the level of variation within the constraints of the tetrapod body plan, it is clear that the information, or patterning system, is both a target and a constraint of possible morphologies. Studying these mechanisms through experimental embryology in model systems can test hypotheses about the underlying process of specific evolutionary changes, as well as lead to new hypotheses that can be tested through the comparative method with the appropriate taxa. Here we describe experiments and results using the chick model system to address the nature of global patterning information in the mesoderm.
The somitic frontier and defining dorso-ventral regions of the body wall
In the dorsal to ventral dimension of the body, regions are traditionally designated as epaxial and hypaxial respectively, based on the innervation of the muscle groups (Romer and Parsons, 1977). Epaxial muscles are served by the dorsal ramus of the spinal nerve, and hypaxial muscles by the ventral ramus. This distinction is very useful for functional descriptions, and has also been used in studies of muscle development (Ordahl and Le Douarin, 1992; Ordahl and Williams, 1998). However, studies of the developmental parameters that control morphogenesis in the embryo are perhaps better served by definitions based on embryonic criteria. In this paper we use the embryonic origin of cells to define dorsal and ventral anatomical compartments (Fig. 1c). This definition is usually, but not always, consistent with the epaxial and hypaxial regions (see below).
Tissues in the dorsal body compartment are composed exclusively of somitic cells and include the vertebra and ribs, the vertebral musculature and the connective tissues in which those tissues form. These structures undergo growth and differentiation essentially in situ, without actively migrating or mixing with other mesodermal populations. The longus colli ventralis in the neck, and the dorsal intercostal muscles are hypaxial based on innervation, but lie in the dorsal body compartment. Both the myocytes of these muscles and their investing connective tissues are formed exclusively from somitic cells. In this compartment, the AP position of the somite is manifest in the distinct morphology of different axial regions (i.e., shape of cervical versus lumbar vertebrae and paraxial muscles).
The ventral body compartment comprises the bulk of the hypaxial muscles, the limbs and ventrolateral body wall. These tissues are composites of lateral plate derived connective tissues and the migratory population of the myotome. Cells from the ventrolateral dermomyotome migrate away from the midline forming a population of axially derived cells that differentiate within the lateral mesoderm. In this ventrolateral population, the AP level of the somite is apparent in different structures of the body wall, limb position and the majority of hypaxial muscles. The boundary between the dorsal and ventral body compartments we refer to as the somitic frontier (Nowicki and Burke, 2000) (Fig. 1c). The somitic frontier marks the transition from a fully somitic cell population to a mixed population of lateral plate and migrating somitic myoblasts. The position of the frontier relative to the dorso-ventral plane varies along the AP axis constituting another aspect of global AP patterning.
Molecular determinants of somite behavior
Differences in somites at each axial level are evident not only in the distinct morphology of the final muscle to which they contribute, but also by the extent of their expansion and the mechanisms by which somite cells migrate across the somitic frontier into the ventral body compartment. Thus, somite cells either contain or acquire information that will insure correct global body pattern in both dorsal and ventral body compartments.
A growing number of genes have been implicated in the specification and behavior of somite cells including migratory behavior of myoblasts at different axial levels. Some genes show regionalized axial expression consistent with a role in influencing migratory behavior (e.g., Scatter Factor; [Théry et al., 1995]: Lbx1, [Dietrich, 1999; Dietrich et al., 1998]). It is not clear, however, how this information is regionalized.
The Hox family of transcription factors is highly conserved throughout Metazoan evolution, and is involved in setting up positional identities along the AP axis (McGinnis and Krumlauf, 1992). In arthropods and vertebrates, Hox genes show an anterior to posterior sequence of expression along the embryonic axis that is colinear with their position along the chromosomes. (Duboule and Dollé, 1989; Graham et al., 1989; Lewis, 1978). This parallel between a pattern along the chromosome and the pattern along the axes of the embryo provides a mechanism for translating local information into global pattern (Duboule, 1994).
In vertebrates, expression of different members of the Hox family is strongly correlated with the morphology of vertebrae along the AP axis (Krumlauf, 1994). Loss and gain-of-function mutations in mice of Hox genes lead to ‘homeotic’ changes in vertebral axial identities (reviewed in Charite, 1994; Crawford, 1995; McGinnis and Krumlauf, 1992). Comparative data demonstrate that Hox genes are also involved in evolutionary changes of the axial formula in vertebrates (Burke et al., 1995; Gaunt, 1994). The boundaries of Hox expression in the paraxial mesoderm map to distinct morphological boundaries along the axis. In other words, Hox expression patterns are independant of segment number and are correlated with transpositional differences between vertebrate taxa.
The concept of a Hox code (Kessel and Gruss, 1991) is based on the sequential expression of Hox genes in an anterior to posterior series that results in a unique combination of Hox expression in any given segment. Each Hox gene is expressed in a variety of tissues though the anterior boundaries of expression do not necessarily align. For instance, the gene boundaries in neural tissues are generally more anterior than boundaries in the paraxial mesoderm, and boundaries in lateral plate mesoderm are often offset from the boundary of the same gene in the somitic mesoderm (Cohn et al., 1997; Oberg and Eichele, 1999). It has been suggested that Hox genes may be responsible for setting up positional information in the lateral plate mesoderm, controlling limb positioning along the axis (see below and Cohn et al., 1997; Rancourt, 1995).
Experimental studies of global patterning in the somitic mesoderm
A number of classical studies have addressed the issue of morphological patterning in the somite mesoderm and described a strong level of autonomous patterning in somite tissues with regard to their global identity (Kieny et al. 1972; Murakami and Nakamura, 1991). Other studies have demonstrated autonomy of Hox expression in mesoderm (cf. Beddington, 1992; Ensini et al., 1998; Itasaki et al., 1996; Kant and Goldstein, 1999). Here, we review the results of experiments designed to assess the patterning information intrinsic to somitic tissue, and whether or not Hox expression acts in parallel with morphological outcome. The data discussed strengthens the correlation of Hox expression with global patterning in paraxial mesoderm, and generates further hypotheses about how Hox genes contribute to the evolution of vertebrate morphology.
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RESULTS AND DISCUSSION |
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Surgical methods and morphological results
We performed orthotopic, heterochronic segmental plate grafts from quail donor embryos to chick hosts, around morphological boundaries (cervical/thoracic) (Fig. 2). More simply stated, donor segmental plate from cervical levels was transplanted to the thoracic level in a host, and vice versa. The use of quail as donor and chick as host provides a means for discriminating donor cells in the host environment due the unique properties of the quail nucleolus (Le Douarin, 1969
). Embryos were examined for skeletal and muscular morphology after fixation 7 days post-operation by clearing and staining with alcian blue for cartilage and MF20 antibody staining for muscle (Developmental Studies Hybridoma Bank, DSHB). Orthotopic, orthochronic surgeries were done for all surgical manipulations to control for the surgical procedure. Full details of all methods can be found in Nowicki and Burke (Nowicki and Burke, 2000).
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In a high percentage of embryos examined for morphological characters, the sclerotomal components of the somite maintained the axial identity of their origin. In cervical to thoracic transplants, ribs were missing and vertebrae were of cervical shape. In the opposite transplant, ectopic ribs appear attached to thoracic type vertebrae at the cervical level. In the dorsal body compartment, muscular morphology was consistent with this—the muscles formed were appropriate to the donor, not the host. For example, in thoracic to cervical transplants, the thoracic intercostals formed at the graft site, and cervical m. longus colli was absent on the operated side. Similarly, in cervical to thoracic transplants, the dorsal m. longus colli of the cervical level was ectopically formed at the thoracic level of the host. However, the ventral body compartment of the cervical donor tissue was incorporated into the ventral body wall abdominal musculature in the thorax of the host. In addition, grafts at the brachial level produced normal limb musculature. To summarize the morphological results, dorsal body compartment musculature maintains its axial identity whereas ventral body compartment musculature does not.
Analysis of Hox expression and other somitic markers
For analysis of the expression of different gene products, embryos were fixed 2–3 days after transplant surgery. Embryos were examined by in situ hybridization for members of the Hox family, including Hox a-6, c-6, c-8 and c-9. In sectioned specimens, muscle markers MyoD and Pax-3 were examined in alternating sections. Examination of Hox expression in whole mount showed that a high percentage of chimeras maintained Hox expression in the graft tissue consistent with its site of origin. This was true for all Hox genes examined. For example, Hox c-8 expression in thoracic to cervical transplants was ectopic in several somites, cranial to the normal anterior boundary of expression (Fig. 3). In contrast, Hox c-8 expression in cervical to thoracic transplants was absent for the approximate length of the graft on the operated side. Sectioned specimens confirm this data, clarifying that somitic cells express (or lack) certain Hox expression after transplant. In Figure 4, a thoracic to brachial transplant, maintenance of expression of Hox c-8 and Hox c-9 can be clearly seen on the left side of each panel as compared to the right, unoperated side. These genes are expressed up to the edge of the dorsal body compartment (*) and expression does not appear to cross the somitic frontier into the ventral body compartment. Somitic cells however, do migrate across the frontier as shown by Pax-3 expression. These cells pass across the frontier and into the limb bud. The fore limb bud does not express Hox c-8 and Hox c-9 in the region of migration, and the cells that cross the frontier do not carry this Hox expression from their parental somite into the lateral plate.
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The ability of cells to aquire new Hox expression is shown by anterior to posterior transplants (cervical-thoracic, Fig. 5). The transplanted tissue (right side of sections) that forms the dorsal compartment does not express Hox c6, which is expressed in this tissue at this axial level in the host (Fig. 5A & B, left side). However, in the flank, populations of cells that express Hox c6 can be seen on both sides of the embryo. Double labeling with quail-specific antibody, (QCPN: Developmental Studies Hybridoma bank) in adjacent sections shows the distribution of graft cells (Fig. 5C–E). The somitic frontier is clearly visible as a border of QCPN-positive cells at the edge of the dorsal compartment (black arrow). The area of Hoxc6 positive cells in the flank is also labeled with QCPN. This indicates that the graft derived cells that cross the somitic frontier, are expressing a new Hox gene appropriate to the lateral plate of the host.
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Significance of dorsal and ventral compartments to tetrapod development: integration of multiple Hox codes
The distinction between dorsal and ventral compartments of the body as defined here is particularly relevant for studies of the distribution of patterning information in the embryo. Development is a dynamic process, and the behavior of cells is largely context dependent, especially in vertebrates. The somite cells that form the dorsal compartment structures are a segregated population and remain isolated from other mesodermal populations. Consistent with this segregation, they also behave as an autonomous unit in terms of both Hox gene expression and morphological pattern. The transplants described here demonstrate the fixation of Hox expression and morphological identity in dorsal compartment somite cells.
Cells contributing to ventral compartment structures are immigrants. That is, they cross the somitic frontier and are integrated with cells from a different embryonic context—the lateral plate mesoderm. Our experiments demonstrate that the migrating cells from transplanted somitic mesoderm adopt the patterning fate of their new environment and contribute to the ventral compartment structures of the host. In terms of Hox gene expression, these cells could present three different behaviors (Fig. 6). First, they might carry a parental Hox code with them (6a). This is clearly not the case as shown by alternate sections in Figure 4. The migrating population labeled by Pax 3 does not express Hox c8 and Hox c9. A second possibility (6b) would be that the migrating cells never have significant Hox expression even before they cross the somitic frontier. A final alternative is that the cells adopt a Hox code appropriate to the lateral plate they migrate into (Fig. 6c). Anterior to posterior transplants suggest that the migrating cells express Hox genes appropriate to the lateral plate, though their parental somites do not (Fig. 5).
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An independent Hox code specific to the lateral plate mesoderm has been suggested by several other studies. When ectopic limb buds are induced by FGF, Hox codes in the lateral plate are altered, while paraxial Hox codes remain intact (Cohn et al., 1997
). These authors argue that the two expression profiles are different because the Hox codes are regulated independently. Coates and Cohn (Coates and Cohn, 1998, 1999) further propose that Hox regulation in the lateral mesoderm may have evolved its independant regulation through association with the endoderm. The splanchnic layer of the lateral plate together with the endoderm develop to form the highly regionalized digestive tract, patterned by colinear Hox expression (Roberts et al., 1995; Roberts, 2000; Yokouchi et al., 1995). In the surgical experiments described here, the behavior of the migratory somitic cells that cross the somitic frontier is consistent with the presence of a lateral plate-specific Hox code. This Hox code would constitute a new patterning environment encountered by the invading somite cells, changing their axial identity from that of their parent somite.
The presence of dorsal and ventral compartments that constitute two different morphogenetic environments helps to explain results from other studies. For instance, many transgenic experiments with members of the myogenic pathway have defects that differentially impact epaxial and hypaxial muscles (for reviews see Dietrich, 1999; Ordahl and Williams, 1998). In the early '90s, several papers described an unexplained positional memory and AP gradient of reporter gene expression in myoblast lineages which was found only in the paravertebrals and intercostal (dorsal compartment), not in the limb or abdominal muscles (Donoghue et al., 1991, 1992; Grieshammer et al., 1992). Myogenesis in the paraxial muscles (dorsal compartment) is dependent on contact with the neural tube and notochord, while limb and abdominal muscles (ventral compartment) are not (Rong et al., 1992).
Significance of patterning mechanisms to the evolution of axial morphology
The combinatorial, colinear Hox code is the result of largely unknown regulatory events that probably act during the movements of gastrulation. Actual expression of Hox genes may be a relatively late manifestation of AP patterning events. However it is clear that upstream factors are already at work and have established an identity that will eventually be read in Hox expression. The medial to lateral segregation of the mesoderm into paraxial and lateral plate populations also occurs as a result of complex movements during gastrulation (e.g., Hatada and Stern, 1994; Psychoyos and Stern, 1996; Schoenwolf et al., 1992). It seems likely that the establishment of Hox expression patterns, and the positioning of cell populations are related, thus insuring harmony between anterior-posterior and medial-lateral patterning axes.
Recently Gaunt (2000) has presented several models for how Hox boundaries may be established in the embryo and how they may undergo evolutionary shifts. Clearly the establishment of independent Hox codes in the paraxial and lateral plate mesoderm would have significance for both the development and the evolution of vertebrates. The paired appendages of gnathostomes arose from ancestors without a significant lateral plate contribution to the body musculature. The limbs and appendicular musculature of tetrapods are a further elaboration of the non-axial musculature. The interaction of two Hox expression domains would provide a system for localizing lateral structures such as limbs and provide additional patterning information for embryonic cells. During individual ontogenies, the ability of the lateral plate to control the patterning fate of myoblasts, demonstrated by the data reported here, provides a level of corrective regulation, or buffering for variations in the axial Hox code. It would also provide flexibility and opportunity for evolutionary changes in the axial formula. A lateral plate that controls the pattern of somite cells reduces the chances of developmental error while greatly increasing the opportunities for genetic changes that lead to successful morphologies.
HoxologyPraise Hox from whom all axes flow,In fish, in flies, and in homo,It makes the snakes unlimblessness,Praise Hox, Pax-6 and distallessby Scott Gilbert
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ACKNOWLEDGMENTS |
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Thanks to Billie Swalla and Jeff Ram for organizing the symposium. The Mf20 antibody developed by D. A. Fischman, and the QCPN antibody developed by M. Bruce and J. A. Carlson were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. This research was supported by NIH R29-HD35932-01 and a March of Dimes Basil O'Connor Starter Scholar Research Award to ACB.
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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.
2 E-mail: acburke{at}wesleyan.edu
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