ReviewThe canonical Wnt pathway in embryonic axis polarity
Introduction
One of the earliest and most important steps occurring during development of all organisms is the establishment of the embryonic axes. In few species, including Drosophila, body axes specification takes place before fertilization [1], while in others, such as the nematode Caenorhabditis elegans, these axes are set up only after fertilization [2]. However, in most organisms, including echinoderms and vertebrates, the first embryonic axis, the animal–vegetal axis, is determined during oogenesis while the dorso–ventral axis is established after fertilization. Many experiments have clearly demonstrated that specification along the embryonic axes is always dictated by polarities established before and/or after fertilization by a combination of localized maternal determinants and cellular interactions. One pathway that has been strongly implicated in axis formation in all phyla is the canonical Wnt pathway. From the diploblast Hydra to the vertebrates, this pathway is among the most evolutionarily well conserved [3], [4]. It is required in a wide variety of cell interactions that play fundamental roles in multiple processes including cell-fate specification, determination of cell polarity and cell migration, and tumorogenesis [5].
In the past decade, the role of the canonical Wnt pathway in axis specification has been best characterized in sea urchin and Xenopus [6], [7]. In each organism, components of the pathway are synthesized during oogenesis, then required shortly after fertilization to specify a critical embryonic axis. In sea urchin the canonical Wnt pathway mediates the specification of the animal–vegetal (AV) axis; whereas, in Xenopus, it is necessary for the establishment of the dorsal–ventral (DV) axis, a completely different axis that is perpendicular to the initial AV polarity. Nevertheless, the mechanisms used by the canonical pathway in both sea urchin and frog to create these axes, respectively, appears to be structurally and functionally well conserved; cytoplasmic and nuclear molecules involved are identical as are their interactions. However, small but nevertheless important differences occur external to or within the pathway that explain why these two distinct axes are formed. After a brief description of the general mechanism of the canonical Wnt signaling, this review will discuss how this pathway is used by two evolutionarily distant organisms, the sea urchin and Xenopus, to specify their embryonic axes.
Section snippets
An overview of the canonical Wnt pathway
Wnt signaling can activate three distinct downstream pathways, the canonical β-catenin-dependent pathway, and two non-canonical pathways. This review however will focus only on the canonical pathway. In general, secreted Wnt ligands act on neighbouring cells, rather than diffusing broadly [8], [9], [10]. The Wnt genes glycoproteins are characterized by special features such as an invariant pattern of 23 highly conserved cysteines residues, twelve of which lie in the last 70 C-terminal
Wnt signaling and the animal–vegetal axis in sea urchin
In sea urchins, the maternally derived canonical Wnt pathway is required to pattern the animal–vegetal (AV) axis. Prior to fertilization, sea urchin oocytes possess a primordial AV polarity that was demonstrated in the past by several embryological experiments [40], [41], [42]. Those experiments further indicated that after fertilization cytoplasmic rearrangements are minimal in sea urchin eggs causing this AV polarity to remain as the first embryonic AV axis (Fig. 2). In addition, in the
Wnt signaling and the dorso–ventral axis in Xenopus
In Xenopus, as in most deuterostomes embryos, the canonical Wnt pathway is required to specify the dorso–ventral (DV) axis, which is established perpendicularly to the primordial AV axis. Experiments performed with various key components of the pathway have demonstrated that, in this organism as in sea urchin, the same cytoplasmic and nuclear molecules, including Dsh, Gsk3β, β-catenin and TCF/LEF, are involved and that they interact and regulate each other in the same way [53], [54].
Conclusion and prospects
The general picture emerging from the above findings is that despite important evolutionary differences, i.e. the dorsal relocalization of Dsh and Wnt11 proteins in response to cortical rotation in Xenopus, many similarities exist between the establishment of the AV axis in echinoderms and the DV axis in vertebrates. In both phyla, specification of these axes is controlled shortly after fertilization by the canonical Wnt pathway which appears structurally and functionally well conserved.
Acknowledgments
The authors acknowledge Athula Wikramanayake, Christian Gache and Thierry Lepage for discussing data ahead of publication. We also thank Drs. Cynthia Bradham and Christine Byrum for critical evaluation of the manuscript. The authors are supported by grants NIH 61464 and HD 14483.
References (71)
- et al.
The polarisation of the anterior–posterior and dorsal–ventral axes during Drosophila oogenesis
Curr Opin Genet Dev
(1999) - et al.
Heads or tails: cell polarity and axis formation in the early Caenorhabditis elegans embryo
Dev Cell
(2002) - et al.
Patterning the sea urchin embryo: gene regulatory networks, signaling pathways, and cellular interactions
Curr Top Dev Biol
(2003) - et al.
Wingless repression of Drosophila Frizzled 2 expression shapes the wingless morphogen gradient in the wing
Cell
(1998) - et al.
Wingless gradient formation in the Drosophila wing
Curr Biol
(2000) - et al.
Direct and long-range action of a wingless morphogen gradient
Cell
(1996) - et al.
Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome
Cell
(1982) - et al.
The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless
Cell
(1987) - et al.
The Frizzled family: receptors for multiple signal transduction pathways
Genome Biol
(2004) - et al.
Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled
Mol Cell
(2003)
Dishevelled: at the crossroads of divergent intracellular signaling pathways
Mech Dev
Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling
Cell
A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling
Curr Biol
Cloning and developmental expression of a novel, secreted Frizzled-related protein from the sea urchin. Strongylocentrotus purpuratus
Mech Dev
LvGroucho and nuclear beta-catenin functionally compete for TCF binding to influence activation of the endomesoderm gene regulatory network in the sea urchin embryo
Dev Biol
TCF is the nuclear effector of the beta-catenin signal that patterns the sea urchin animal–vegetal axis
Dev Biol
Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development
Dev Cell
Molecular patterning along the sea urchin animal–vegetal axis
Int Rev Cytol
GSK-3: new thoughts on an old enzyme
Dev Biol
Heads or tails? Amphioxus and the evolution of anterior–posterior patterning in deuterostomes
Dev Biol
Axis formation—beta-catenin catches a Wnt
Cell
Control of intercalation is cell-autonomous in the notochord of Ciona intestinalis
Dev Biol
Subcortical rotation in Xenopus eggs: an early step in embryonic axis specification
Dev Biol
Maternal Wnt11 activates the canonical Wnt signaling pathway required for axis formation in Xenopus embryos
Cell
Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos
Mech Dev
A genetic regulatory network for Xenopus mesendoderm formation
Dev Biol
Wingless signaling: the inconvenient complexities of life
Curr Biol
WNT signalling molecules act in axis formation in the diploblastic metazoan Hydra
Nature
Wnt signaling: a common theme in animal development
Genes Dev
Move it or lose it: axis specification in Xenopus
Development
The nucleotide sequence of the human int-1 mammary oncogene; evolutionary conservation of coding and non-coding sequences
EMBO J
Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos
Genes Dev
Phylogenetic relationships and developmental expression of three sea urchin Wnt genes
Mol Biol Evol
Nuclear beta-catenin-dependent Wnt8 signaling in vegetal cells of the early sea urchin embryo regulates gastrulation and differentiation of endoderm and mesodermal cell lineages
Genesis
Cited by (55)
Elevated glucose levels impair the WNT/β-catenin pathway via the activation of the hexosamine biosynthesis pathway in endometrial cancer
2016, Journal of Steroid Biochemistry and Molecular BiologyMolecular asymmetry in the 8-cell stage Xenopus tropicalis embryo described by single blastomere transcript sequencing
2015, Developmental BiologyCitation Excerpt :In many organisms, these early events are accomplished by the localization or sequestration of maternally synthesized proteins and mRNA (Danilchik et al., 2006). Mechanisms vary in non-vertebrate species (Gonczy and Rose, 2005; Kugler and Lasko, 2009; Steinhauer and Kalderon, 2006), but in vertebrates, the animal–vegetal axis is set up during oocyte maturation, and the dorsal–ventral axis is established at or shortly after fertilization (Croce and McClay, 2006). In Xenopus, the oocyte develops with radial symmetry around the animal–vegetal axis between the darkly pigmented animal pole and the lightly pigmented vegetal pole (Kageura, 1997).
Expression of skeletogenic genes during arm regeneration in the brittle star Amphiura filiformis
2013, Gene Expression PatternsPolycyclic aromatic hydrocarbons and dibutyl phthalate disrupt dorsal-ventral axis determination via the Wnt/β-catenin signaling pathway in zebrafish embryos
2012, Aquatic ToxicologyCitation Excerpt :The Wnt/β-catenin signaling pathway, highly conserved through evolution, has been implicated in axis specification in both vertebrates and invertebrates (Cadigan and Nusse, 1997; Ferkey and Kimelman, 2000; Holland, 2002; Petersen and Reddien, 2009). This pathway regulates β-catenin stability and controls the expression of target genes that regulate cell fate and differentiation, cell proliferation and migration, as well as apoptosis and tumoregenesis (Croce and McClay, 2006; Kikuchi, 2000; Moon et al., 2002). The regulation of β-catenin by the constitutively active kinase GSK-3β (glycogen synthase kinase-3β), as part of a complex of other proteins known as the “destruction complex,” mediates the formation of dorsal signaling centers in teleost embryos and thereby plays a crucial role in dorsal–ventral axis formation.
Development and mechanistic explanation
2012, Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical SciencesCitation Excerpt :It is important to have in mind that Xenopus, as a model organism, has been taken to represent not only its own developmental process of axes formation but also some of the most important stages associated to this process—stages conserved across all vertebrates (e.g. the formation of the Nieuwkoop center, the formation of the organizer, the beginning of gastrulation, etc.); this paradigmatic dimension of Xenopus can be seen in important textbooks such as Gilbert (2000). Having said this, I would like to mention that axes formation in vertebrates, as illustrated in Xenopus, arises progressively through a sequence of interactions among neighbor cells (Croce & McClay, 2006). This is then an instance of conditional development in which the cell’s fate is determined by the action of its neighbors; this process has been referred as induction (Kuroda et al., 2004; Wessely, Kim, Tran, Fuentealba, & De Robertis, 2005; Vonica & Gumbiner, 2007).