U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

The Role of Wnt Signaling in Vertebrate Head Induction and the Organizer-Gradient Model Dualism

and .

The prevailing model for anteroposterior (AP) axis formation during vertebrate embryo genesis implies distinct organizer regions inducing head and trunk structures, respectively. A gradient of posteriorizing activity (transformer) which regulates AP patterning of the neuraxis has been suggested on the other hand by classical studies using amphibian embryos. Here, we will review the roles of Wnt signaling during head formation in various vertebrate model organisms. Early in vertebrate embryogenesis, organizer (and thus head) formation depends on a Wnt-type b-catenin-mediated signal. During gastrulation, posteriorizing Wnt/b-catenin signaling antagonizes the head organizer whose distinguishing feature is the secretion of Wnt inhibitors. The interplay between head organizer-derived Wnt inhibitors and posteriorizing Wnts establishes a gradient of Wnt/b-catenin activity that regulates AP patterning of the vertebrate gastrula. Thus, the concepts of head and trunk organizer and of the transformer gradient are reconciled in a dualistic view of AP axis formation.


In vertebrates, the two main body axes, anteroposterior (AP) and dorsoventral (DV), are progressively established during early embryogenesis. The anterior extremity of a vertebrate is defined by its head, a complex structure formed from derivatives of all germ layers. The vertebrate head is characterized by an elaborate segmented brain, sensory organs and structural components such as skull bones, teeth and facial muscles. These features distinguish vertebrates even from their closest nonvertebrate relatives, the cephalochordates.1 Here, we will review the different and sometimes opposing roles played by growth factors of the Wnt family during head formation with special emphasis on the emerging notion that inhibition of Wnt/ β-catenin signaling is crucially required for anterior specification. As we will discuss below, the seemingly different organizer and gradient models for AP axis formation are reconciled in light of the emerging underlying molecular mechanism.

The Vertebrate Organizer

Fundamental progress in understanding embryonic axis formation was made in the 1920s when the embryologists Hilde Mangold and Hans Spemann demonstrated the extraordinary inductive potency of the amphibian dorsal blastopore lip by performing transplantation experiments on newt embryos. They explanted the comparably small dorsal lip region from a donor gastrula and grafted it to the ventral side of a host. This treatment induced a complete secondary embryonic axis, including a well-patterned head, within the host embryo. Only few structures of the secondary axis were derived from the transplanted tissue while most of the ectopic tissues were derived from the host. Mangold and Spemann concluded that the transplanted cells had induced and organized the surrounding host tissue nonautonomously to become part of the secondary axis.2

Tissues corresponding to Spemann's organizer have since been identified in chick, fish, rabbit and mouse.37 The organizer regions of all these vertebrates show comparable tissue fates and are able to induce twinning when transplanted to ectopic locations in host embryos.35,710 Thus, the vertebrate organizer appears to be an evolutionary conserved structure with a primary function in embryonic axis formation.

Classical Models for Anteroposterior Axis Formation

At least three different tissues derived from the organizer are distinguishable at neurula stages (from anterior to posterior): (1) the anterior endoderm (AE) which will give rise to the liver at later stages, (2) the prechordal mesendoderm (PME) which will differentiate into head mesenchyme, head and eye muscles and foregut and (3) the chordamesoderm (CM) which will give rise to the notochord. Together, these organizer derivatives are referred to as axial mesendoderm.

In the 1930s, Spemann's colleague Otto Mangold dissected the archenteron roof (containing the axial mesendoderm) of early newt neurulae into four transversal segments and implanted these pieces into the blastocoel of early gastrulae. As in the Mangold-Spemann experiment, the grafts were able to induce ectopic structures in the host embryos. Their inductive potential, however, seemed to be more restricted compared with early organizer grafts: The anteriormost grafts (containing AE) only induced ectopic balancers and parts of the oral apparatus while grafts containing PME and anterior CM frequently induced ectopic head structures such as balancers, eyes, otic vesicles, fore- and midbrain; grafts containing medial CM induced ectopic trunks including hindbrain and spinal cord tissue and the posteriormost type of grafts (containing posterior CM) induced ectopic tails (Fig. 1A). Mangold concluded that derivatives of the organizer differ not only in fate but also in inducing potential, with anterior organizer inducing head structures and posterior organizer inducing trunk and tail structures.11 Similarily, Einsteck assays using early gastrula lips resulted in the formation of complete secondary axes including heads while late gastrula lips only induced secondary trunks (Fig. 1B). Taken together, these results suggested that the organizer consists of distinct head- and trunkorganizing regions and that the region between PME and anterior CM harbors the strongest head-inducing potential.

Figure 1. Regionally specific induction by Spemann's organizer.

Figure 1

Regionally specific induction by Spemann's organizer. (A) Mangold's experiment demonstrating regionally specific induction by axial mesendoderm. Transversal segments of the archenteron roof of newt neurulae (left) were implanted into the blastocoel of (more...)

An alternative model for AP axis formation was introduced in the 1950s by the “Dutch school” of embryologists represented by Pieter Nieuwkoop and colleagues.12 Nieuwkoop implanted folds of competent ectoderm into prospective neural plates of amphibian embryos at different AP levels. Analysis of the grafts revealed that folds implanted at the forebrain level had differentiated exclusively into anterior neural structures (such as nasal pits, pineal gland, eyes and forebrain) while folds implanted at the hindbrain level had differentiated into hindbrain at their base and into forebrain distally. Folds implanted at the spinal cord level had differentiated into spinal cord at their base, into hindbrain medially and into forebrain distally (Fig. 2A). Comparable results were obtained using flattened explants of ectoderm juxtaposed with fragments of CM.13 Based on these observations Nieuwkoop proposed the sequential activity of two signals (Fig. 2B): First, a signal from the dorsal mesoderm (organizer) induces the overlying ectoderm to become neuroectoderm of anterior character (activation step). Second, a signal which is absent from the anterior of the embryo and becomes increasingly stronger posteriorly confers progressively posterior identity to the corresponding part of the neural plate (transformation step).

Figure 2. Classical models for AP patterning.

Figure 2

Classical models for AP patterning. In all schemes, anterior points to the left, dorsal to the top. (A) Sagittal section of an early neurula newt embryo with ectodermal folds implanted at three different AP levels of the neural plate (1°,2°,3°). (more...)

Similarly, a model based on the activity of two opposing activities was devised by the “Finnish school” of embryologists. According to this model, AP axial patterning is regulated by the concentration ratio between an archencephalic (forebrain-type) and a spinocaudal (posteriorizing/mesodermalizing) inducer (Fig. 2C).14,15 It is of note that both Nieuwkoops two-step and the two-inducer model predict gradients of posteriorizing factors. As we will discuss below, organizer and gradient models merely reflect different perspectives of the same phenomenon.

Wnt/β-catenin Signaling Antagonizes the Vertebrate Head Organizer

Gain- and loss-of-function approaches in Xenopus and zebrafish have revealed that Wnt/ β-catenin-type signaling is necessary and sufficient for organizer induction and thus, indirectly, for head formation during an early phase of embryogenesis (reviewed in chapter 4; refs. 16,17). The competence of Xenopus and zebrafish embryos to respond to Wnt signals changes dramatically after the midblastula transition (MBT) when zygotic transcription starts. Post-MBT Wnt/ β-catenin signaling does not have organizer-inducing properties anymore but it antagonizes the head organizer and confers posteriorizing activity: Overexpression of various Wnts, the Wnt transducers β-catenin or XTCF-3, or treatment with the artificial Wnt pathway activator Li+ after MBT lead to repression of anterior and concomittant induction of posterior neural markers and suppression of head development (Fig. 3).1832 Wnt/β-catenin signaling is able to counteract Xenopus head organizer activity at least until the end of gastrulation as revealed by experiments with embryos carrying an inducible XWnt-8 transgene.33 A posteriorizing role for Wnts is also suggested by studies on transgenic mice ectopically expressing chick Wnt-8C and by Li treatment of gastrulating chick embryos.34,35

Figure 3. Wnts posteriorize Xenopus embryos.

Figure 3

Wnts posteriorize Xenopus embryos. Activation of the Wnt/β-catenin pathway (+Wnt) leads to headless tadpoles (lower panel); its inhibition (-Wnt) results in enlargement of anterior and concomittant reduction of trunk structures (upper panel). (more...)

Wnt/β-catenin signaling not only suppresses anterior but is also required for posterior development: Overexpression of Wnt antagonists in Xenopus and zebrafish, respectively, results in the formation of embryos with enlarged head structures and shortened trunks (Fig. 3).3646 Similarly, both overexpression of GSK3β in Xenopus anterior ectoderm and depletion of β-catenin from this region using morpholino antisense oligos elicits neural anteriorization.47,48 Mice mutant for Wnt-3A, Wnt-5A, LEF-1 and TCF-1 -encoding nuclear transducers of Wnt signaling-, and LRP6 -encoding a Wnt coreceptor- show posterior truncations, providing genetic evidence for the requirement for Wnts in posteriorization.4952 Pronounced trunk defects are also observed in zebrafish lacking Wnt-8 function.53 Interestingly, allelic combinations of mouse Wnt-3A- and Vestigial tail, a hypomorphic mutation of Wnt-3A, display dose-dependent posterior truncations suggesting a requirement for increasing levels of Wnt signaling to specify increasingly more posterior fates.54 Likewise, posterior neural fates are progressively deleted in zebrafish by increasing doses of morpholino oligos.55

Thus, Wnts elicit phenotypically opposing effects with early signaling promoting and late signaling counteracting head formation. This complicates the phenotypic interpretation of global gain- and loss-of-function experiments and advocates the importance of manipulating gene expression in defined time windows. The change of cellular competence to respond to Wnt signals (from organizer induction to head antagonism) does not seem to be caused by the employment of a different (noncanonical) Wnt pathway but by a change of nuclear cofactors. 28,31

Tissues with Posteriorizing Activity Express Wnts

Nieuwkoop and colleagues have described graded transforming activity residing within posterior axial mesoderm (CM) and this has been confirmed by tissue recombination experiments in Xenopus, mouse and chick.5659 However, studies in Xenopus, chick and zebrafish have also revealed a posteriorizing function of nonaxial tissues.6064 All tissues implicated in posteriorization express at least one member of the Wnt family during gastrulation (Table 1).

Table 1. Wnt expression in vertebrate gastrulae.

Table 1

Wnt expression in vertebrate gastrulae.

The Two Inhibitor Model for Head Induction

How does the notion of separate head and trunk organizers relate to the posteriorizing activity of post-MBT Wnt signaling? The vertebrate organizer expresses a large number of secreted growth factors and growth factor antagonists which continue to be expressed in the axial mesendoderm in different patterns. It is well established that inhibitors of bone morphogenetic proteins (BMPs—a TGFβ subfamily) which are expressed all along the AP axis (Table 2) mediate the dorsalizing and neural inducing activity of Spemann's organizer in amphibians (reviewed in ref. 65). Ectopic expression of BMP antagonists on the ventral side of Xenopus embryos induces secondary trunks lacking anterior neural structures up to the hindbrain suggesting that trunk organizer function is mediated by BMP inhibition (Fig. 4A). A distinguishing feature of the anterior derivatives of the organizer (AE and PME) is the expression of Wnt inhibitors (Table 2; reviewed in refs. 66,67). Coexpression of BMP and Wnt antagonists induces complete secondary axes including heads with anterior neural structures (Fig. 4B).38,42 Based on these observations, the “two inhibitor model” for head induction has been proposed: The head organizer functions by simultaneously antagonizing BMP and Wnt signaling while the trunk organizer only antagonizes BMP signaling (Fig. 4C).38,66

Table 2. Regional-specific expression of Secreted Organizer Effectors in Xenopus.

Table 2

Regional-specific expression of Secreted Organizer Effectors in Xenopus.

Figure 4. The two inhibitor model for head induction.

Figure 4

The two inhibitor model for head induction. (A) Ectopic BMP antagonism results in trunk duplication, (B) a combination of BMP and Wnt antagonism induces heads. (C) Diagram representing the two inhibitor model.

In amphibians, heterotopic grafting studies have located the strongest head-inducing potential to PME and anterior CM and ablation studies have proven a requirement for this part of the organizer in head formation.11,68 Grafts of corresponding regions in chick and zebrafish also result in anterior neural induction, emphasizing the instructive role of anterior axial mesendoderm, a major source of Wnt inhibitors, in head development (Fig. 5).9,69

Figure 5. Comparative scheme of vertebrate gastrulae.

Figure 5

Comparative scheme of vertebrate gastrulae. Simplified schemes of midsagittal sections through (A) Xenopus, (B) zebrafish, (C) chick and (D) mouse gastrulae. Axial mesendodermal tissues are shown in dark grey; expression of Wnt inhibitors is indicated (more...)

Supporting the two inhibitor model, inhibition of Wnt signaling is necessary in vivo for formation of anterior neural structures in Xenopus, zebrafish and mouse: Inhibition of the secreted Wnt antagonist Dickkopf1 (Dkk-1) in Xenopus using neutralizing antibodies as well as genetic inactivation of the Wnt antagonists TCF-3 and axin1 in the zebrafish headless and masterblind mutants, respectively, all result in microcephalic embryos.27,42,70,71 A targeted knockout of the Dkk-1 gene in mouse leads to embryos completely lacking rostral head structures.72

Interestingly, a very recent study has revealed that instructive signaling by insulin-like growth factors (IGFs) is necessary and sufficient for anterior neural induction in Xenopus.73 In line with the two inhibitor model, IGF signaling has been demonstrated to counteract the Wnt/β-catenin pathway. Epistatically, this inhibition seems to occur between GSK3β and β-catenin and one of the next important steps will certainly be to analyze the underlying biochemical mechanism. Furthermore, it remains to be investigated whether Wnt inhibition is the major effect of IGF signaling in head induction or whether IGFs perform other independent functions beyond Wnt inhibition—a likely possibility given that, in contrast to known Wnt inhibitors, IGFs are able to ectopically induce anterior structures such as eyes and cement glands.

Similar to the head, the vertebrate heart is derived from anterior regions of the gastrulating embryo. Although the definitive heart ends up in a ventral position, its precursor -the cardiogenic mesoderm- is located adjacent to the PME, in a region with low levels of Wnt/β- catenin signaling. Three recent studies using chick and Xenopus embryos have highlighted a central role of Wnt inhibition in heart specification, lending further support to the two inhibitor model (reviewed in chapter 11).7476 Notably, ectopic expression of Wnt-8C in transgenic mouse embryos results in reduced heart and foregut structures suggesting that low levels of Wnt signaling are required for anterior specification of all germ layers.34

Anterior Organizing Centers Express Wnt Inhibitors

As discussed above, anterior axial mesendoderm functions as head organizer in amphibians, zebrafish and chick (Fig. 5AC).9,11,69 In the mouse, however, grafts of both late and early gastrula organizer regions only induce secondary embryonic axes lacking anterior neural structures. 7,77 The murine anterior visceral endoderm (AVE), an extraembryonic structure derived from the distal tip of the early embryo, shifts anteriorly before the onset of gastrulation until it underlies the prospective anterior neural plate (Fig. 5D).7880 Remarkably, the AVE has been found to express many organizer genes involved in anterior specification and its surgical ablation results in anterior defects.78,79 Analyses of chimeric mice in which the function of AVEexpressed genes is specifically disrupted in extraembryonic tissues has supported the notion that the AVE is essential for head formation (for reviews see refs. 79,81). Yet, AVE alone is not able to ectopically induce anterior neural markers when grafted heterotopically.77 Recombination of ectodermal explants with AVE does not result in anterior neural induction although posterior markers become suppressed, suggesting a rather permissive role for AVE in anterior development.82 It is likely that this suppression of posterior fates is mediated by Wnt antagonism and, in line with this hypothesis, the AVE secretes the Wnt antagonists Cerberus-like (Cer-l) and Dkk-1.8386 As mentioned above, Dkk-1-/- mice are headless but the loss of Cer-l function does not elicit head defects.72,8791 Thus, if Wnt inhibition is an essential function of AVE it may be mediated redundantly.

An AVE-like role has been suggested for the anterior hypoblast of the chick embryo which is also a source of several Wnt inhibitors (Fig. 5C). This tissue is not able to stably induce forebrain identity in naïve chick epiblast, but it transiently induces early neural markers and directs epiblast movements.92,93 A model has been proposed in which the role of the anterior hypoblast (and the murine AVE) is to protect presumptive anterior neuroectoderm from posteriorizing activities.82,93 Yet, despite emerging similarities between the mammalian AVE and the chick anterior hypoblast (gene expression, pregastrulation movements), there are fundamental differences between these tissues with regard to their inducing abilities as revealed by heterospecies transplantations: Rabbit anterior hypoblast is able to stably induce anterior neural fates upon transplantation under chick epiblast, compared to only transient induction of some pre-neural markers by chick anterior hypoblast.92,93 The molecular basis for these differences remains elusive.

If the role of the AVE in head induction is permissive, which structures do actually provide instructive head-inducing signals in the mouse embryo? The earlier observation that mouse organizer grafts fail to induce complete embryonic axes including anterior neural structures has been challenged recently: Transplantation of mouse or rabbit organizers into chick host embryos results in formation of complete secondary axes including forebrain structures, indicating that, in principle, the mammalian organizer harbors the capacity for anterior neural induction. 94 Very recently, Tam and colleagues have described induction of complete secondary axes in mouse embryos by mid-gastrula stage organizers.10 Thus, the early gastrula organizer (EGO; see ref. 77) may not yet have acquired full head-inducing potential while the late gastrula organizer (see ref. 7) may have lost its head-inducing potential already. A similar situation is encountered in chick: Neither the anterior primitive streak of the early chick gastrula nor the node after the emigration of the head process are able to induce complete secondary embryonic axes.95,96 Finally, it has been demonstrated by ablation that anterior axial mesendoderm is not only sufficient but also required for forebrain development in mice.97

Ablation of a single row of cells from the ectoderm that borders the neural plate anteriorly in the zebrafish gastrula (row-1 cells) results in head defects (Fig. 5B), indicating the presence of another early anterior-inducing center.98 Notably, a Wnt inhibitor of the sFRP (secreted Frizzled-related protein) class has been identified as mediator of row-1 function (see Note Added in Proof). Taken together, all of the tissues implicated in anterior neural induction in various species are sources of secreted Wnt inhibitors.

A Transforming Gradient of Wnt/β-catenin Activity Regulates AP Neural Patterning

While Spemann and coworkers suggested distinct head- and trunk-inducing regions within the embryo—and this view is in agreement with the two-inhibitor model for vertebrate head induction—the AP axis of the embryo is patterned by a posteriorizing gradient of a transformer according to the activation-transformation model proposed by Nieuwkoop and colleagues. Clearly, the two-inhibitor model—in its simple form—is not sufficient to explain regional AP patterning of the neuraxis like Nieuwkoop's model. To reconcile the two-inhibitor and the activation-transformation model we have investigated recently whether Wnts may constitute the transforming signal.32 We found that in Xenopus (1) Wnts posteriorize neuroectoderm dose-dependently, (2) Wnt/β-catenin signaling is required for AP ectodermal patterning during gastrulation and (3) Wnts are able to signal directly and over a distance within neuroectoderm, conferring polar AP neural pattern to neuralized ectodermal explants and in vivo. Importantly, an endogenous AP gradient of Wnt/β-catenin signaling was detected in the presumptive neural plate of the Xenopus gastrula. These data support a model in which a posteriorizing activity gradient of Wnt/β-catenin signaling is established during gastrulation by the interplay of head organizer-derived Wnt inhibitors and posteriorly expressed Wnts (Fig. 6). Furthermore, they suggest that Wnts may act as morphogens in vertebrates. However, a recent study describes nonautonomous induction of posterior neural markers following overexpression of β-catenin in Xenopus ectodermal explants.29 Differences in the experimental setup may explain this apparent discrepancy. In particular, we have used an earlier readout in our experimental approach.

Figure 6. Simplified model for AP patterning of neuroectoderm by a Wnt activity gradient.

Figure 6

Simplified model for AP patterning of neuroectoderm by a Wnt activity gradient. Wnts (black) and Wnt inhibitors are expressed in the axial mesendoderm underlying the neuroectoderm. The expression of Wnts and Wnt inhibitors in the neuroectoderm is not (more...)

In vivo, the expression domains of regional neural marker genes change following modulation of Wnt signaling: Forced activation of the Wnt/β-catenin pathway after the MBT results in a loss of anterior neural fates while, conversely, an expansion of anterior at the expense of posterior neural markers is observed upon overexpression of Wnt antagonists. Yet, the expression domains of these markers always respect certain boundaries and do never expand throughout the entire neural plate.32 This suggests that the competence of neural cells to respond to Wnts is regionally restricted. An organizer-independent ectodermal AP prepattern which depends on differential competence of the epiblast has been described in zebrafish.99 Besides Wnts, other signaling molecules such as fibroblast growth factors (FGFs) and retinoic acid (RA) have been implicated in posteriorization which may regulate cellular competence (see refs. 100102 for reviews). FGFs are potent posteriorizing agents (e. g. see ref. 103), yet, Wnt antagonists rescue FGF-induced posteriorization in Xenopus, suggesting that this effect is mediated —at least in part—indirectly through Wnts.23,27 Interestingly, a recent study in chick suggests that FGFs are required during gastrulation to maintain a population of neural progenitors within Hensen's node.104 The authors propose a model in which FGFs are not a transforming agent but define a niche for neural stem cells in the posteriorly regressing organizer where cells remain exposed to the true transformer (discussed in ref. 105). Obviously, Wnts are good candidates for this signal. Taken together, AP neural patterning is regulated by Wnt/β-catenin signaling while RA and FGFs may also contribute to this process, maybe by regulating the competence of neural cells to respond to posteriorizing Wnt signals.

Wnt Signaling and Gastrulation Movements

Zebrafish silberblick mutants display mild cyclopia and other head midline defects.106 Interestingly, a mutation in the Wnt-11 locus has been identified as the cause of this phenotype.107 Yet, the silberblick head defects are unlikely to result from a failure in head induction or AP patterning: Several recent studies in Xenopus and zebrafish have provided strong evidence for a noncanonical, β-catenin-independent Wnt pathway (involving Wnt-11 and Dishevelled) regulating the convergent-and-extension movements characteristic of vertebrate gastrulation (see Chapter 1).107114 Impaired elongation of axial mesendoderm which is a source of midline patterning signals is the most probable explanation for the silberblick phenotype. Overexpression of the Wnt inhibitor Crescent/Frzb2 (Crs) in Xenopus elicits a comparable phenotype, suggesting that Crs inhibits Wnt-11-like signals.115,116 Remarkably, the neural plate is anteriorized in Crs-expressing embryos.116 Thus, Crs may inhibit a spectrum of different Wnts implicated in canonical and noncanonical signaling. In conclusion, head defects may arise due to inhibition of noncanonical Wnt signaling.

Later Roles of Wnts

At later stages of vertebrate development, Wnts and Wnt inhibitors are expressed in complex patterns and perform various roles depending on their timing and location of expression. Almost all Wnts and many Wnt modulators are differentially expressed in the embryonic cen- tral nervous system.50,117119 Not much is known concerning the precise functions of Wnt signaling at these stages. They have been implicated in pattern refinement and subregionalisation, as retrograde signals in axon remodeling and synaptic differentiation and in modulating apoptosis (refs. 120,121). Wnt-1 which is expressed in the mesencephalon is required for maintaining the midbrain-hindbrain boundary (isthmic) organizer and for the development of the cerebellum, an isthmus-derived structure (reviewed in refs. 122,123). A local Wnt-3A signal from the developing cerebral cortex promotes cell proliferation during hippocampus formation.124,125

Gain- and loss-of-function analyses in all vertebrate model organisms have revealed that Wnt signals are crucial for formation and specification of the neural crest, a specialized cell population that is induced at the lateral edges of the neural plate and becomes localized to the dorsalmost region of the neural tube.24,25,126129 Neural crest cells undergo an epithelial-mesenchymal transition, migrate to many different targets within the developing embryo and give rise to a variety of different cell types (reviewed in ref. 130). The cranial neural crest populates the branchial arches, gives rise to cranial ganglia and craniofacial cartilage and bone and is therefore of central importance for later events in head formation.130133 Many Wnts are predominantly expressed in dorsal regions of the neural tube (e. g. in Xenopus: XWnt-1—midbrain, dorsal neural tube; XWnt-2B—dorsal forebrain/midbrain boundary; XWnt-3A—dorsal neural tube; XWnt-7B—dorsal neural tube; XWnt-8B—dorsal di- and mesencephalon, forebrain/midbrain boundary).25,134136 Mouse Wnt-1-/-;Wnt-3A-/- double mutants display, besides many other defects, a dramatic reduction of neural crest and severe craniofacial abnormalities. 126 Interestingly, Wnt-5A-/- mutant mice also have abnormally shaped heads. Wnt-5A—which is considered not to activate the canonical Wnt/β-catenin pathway because it belongs to a distinct class of Wnts—is expressed in the outgrowing first branchial arch and in outgrowing facial primordia. It has been suggested that a Wnt-5A pathway is generally involved in regulating the outgrowth of extending structures.50

Taken together, Wnts play various roles during later stages of head development which may be positive as described for midbrain, hippocampus and neural crest development. However, the large number of Wnts and Wnt modulators expressed in a highly regionalized manner highlights the need for further detailed investigations.

Conclusions and Outlook

At least three phases of Wnt signaling can be distinguished during vertebrate head formation. First, early β-catenin-dependent signaling plays a central role in organizer induction which is a prerequisite for head formation. Second, Wnt/β-catenin signaling antagonizes the head organizer during gastrulation. Different anterior-organizing centers have been identified in vertebrate gastrulae and all of them secrete Wnt antagonists. The interplay of these antagonists with posteriorizing Wnts may establish a tranforming activity gradient of Wnt/β-catenin signaling which regulates AP neural patterning. Based on these molecular data, we propose that Spemann's concept of separate head and trunk organizers and Nieuwkoop's transforming gradient do not contradict each other but represent two different views of AP axis formation: Like an electron will appear as a wave or a particle, AP patterning appears as regulated by organizers or gradients, depending on the experimental approach.

While Wnt/β-catenin signaling regulates AP patterning, noncanonical Wnt-11-type signaling promotes axial elongation and interference with this pathway may affect head formation indirectly. In the third and least characterized phase of Wnt signaling, multiple Wnts are expressed in a highly regionalized fashion. Wnts play important roles in the regional patterning of the brain and in the specification of neural crest which is essential for later steps of craniofacial development.

In the future, it will be crucial to modulate Wnt signaling during defined intervals and in restricted regions in order to specifically target distinct Wnt functions. First steps in this direc- tion have been made by using inducible transgenes and tissue transplantation approaches.28,29,31 33 Furthermore, the identification of transcriptional targets of Wnt signaling will be of great interest. In particular, the identification of genes activated by later (e.g. posteriorizing) Wnt/β-catenin signaling is in its very beginnings.26

Note Added in Proof

While this chapter was reviewed, a study using chick embryos has been published which lends support to the idea that a gradient of Wnt/β-catenin signaling regulates AP patterning of the early neural plate (Nordström U, Jessell TM, Edlund T. Progressive induction of caudal neural character by graded Wnt signaling. Nat Neurosci 2002; 5:525–532). Furthermore, a Frzb-like Wnt inhibitor (Tlc) was identified which mediates the anteriorizing function of row- 1 cells in zebrafish (Houart C, Caneparo L, Heisenberg C et al. Establishment of the telencephalon during gastrulation by local antagonism of Wnt signaling. Neuron 2002; 35:255– 265). This and another study suggest that in the late zebrafish gastrula Wnt signaling regulates patterning between fore- and midbrain (Kim SH, Shin J, Park HC et al. Specification of an anterior neuroectoderm patterning by Frizzled8a-mediated Wnt8b signalling during late gastrulation in zebrafish. Development 2002; 129:4443–4455). Recently, Wnt6 expression has been described in chick (Schubert FR, Mootoosamy RC, Walters EH et al. Wnt6 marks sites of epithelial transformations in the chick embry. Mech Dev 2002; 114:143–148) and has been proposed to act as a direct inducer of neural crest (Garcia-Castro MI, Marcelle C, Bronner- Fraser M. Ectodermal Wnt function as a neural crest inducer. Science 2002; 297:848–851).


We apologize to all researchers whose work we could not cite due to space constraints. We thank Dr. Gary Davidson for helpful comments on the manuscript.


Shimeld SM, Holland PW. Vertebrate innovations. Proc Natl Acad Sci USA. 2000;97:4449–4452. [PMC free article: PMC34320] [PubMed: 10781042]
Spemann H, Mangold H. Über Induktion von Embryonalanlagen durch Implantation artfremder Organisatoren. Arch Mikrosk Anat Entwicklungsmechan. 1924;100:599–638.
Waddington CH. Induction by the primitive streak and its derivatives in the chick. J Exp Zool. 1933;10:38–46.
Oppenheimer JM. Transplantation experiments on developing teleosts (Fundulus and Perca). J Exp Zool. 1936;72:409–437.
Waddington C. Organizers in mammalian development. Nature. 1936;138:125.
Blum M, Gaunt SJ, Cho KW. et al. Gastrulation in the mouse: the role of the homeobox gene goosecoid. Cell. 1992;69:1097–1106. [PubMed: 1352187]
Beddington RS. Induction of a second neural axis by the mouse node. Development. 1994;120:613–620. [PubMed: 8162859]
Shih J, Fraser SE. Characterizing the zebrafish organizer: microsurgical analysis at the early-shield stage. Development. 1996;122:1313–1322. [PubMed: 8620858]
Saúde L, Woolley K, Martin P. et al. Axis-inducing activities and cell fates of the zebrafish organizer. Development. 2000;127:3407–3417. [PubMed: 10903167]
Kinder SJ, Tsang TE, Wakamiya M. et al. The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development. 2001;128:3623–3634. [PubMed: 11566865]
Mangold O. Über die Induktionsfähigkeit der verschiedenen Bezirke der Neurula von Urodelen. Naturwissenschaften. 1933;21:761–766.
Nieuwkoop PD, Botterenbrood EC, Kremer A. et al. Activation and organization of the central nervous system in amphibians. J Exp Zool. 1952;120:1–108.
Nieuwkoop PD, Nigtevecht GV. Neural activation and transformation in explants of competent ectoderm under the influence of fragments of anterior notochord in urodeles. J Embryol Exp Morph. 1954;2:175–193.
Saxén L, Toivonen S. The two-gradient hypothesis in primary induction: The combined effect of two types of inducers mixed in different ratios. J Embryol Exp Morph. 1961;9:514–533. [PubMed: 14497697]
Toivonen S, Saxén L. Morphogenetic interaction of presumptive neural and mesodermal cells mixed in different ratios. Science. 1968;159:539–540. [PubMed: 5635157]
Schier AF. Axis formation and patterning in zebrafish. Curr Opin Genet Dev. 2001;11:393–404. [PubMed: 11448625]
Solnica-Krezel L, Driever W. The role of the homeodomain protein Bozozok in zebrafish axis formation. Int J Dev Biol. 2001;45:299–310. [PubMed: 11291860]
Christian JL, Moon RT. Interactions between Xwnt-8 and Spemann organizer signaling pathways generate dorsoventral pattern in the embryonic mesoderm of Xenopus. Genes Dev. 1993;7:13–28. [PubMed: 8422982]
Kelly GM, Erezyilmaz DF, Moon RT. Induction of a secondary embryonic axis in zebrafish occurs following the overexpression of β-catenin. Mech Dev. 1995;53:261–273. [PubMed: 8562427]
Kelly GM, Greenstein P, Erezyilmaz DF. et al. Zebrafish wnt8 and wnt8b share a common activity but are involved in distinct developmental pathways. Development. 1995;121:1787–1799. [PubMed: 7600994]
McGrew LL, Lai CJ, Moon RT. Specification of the anteroposterior neural axis through synergistic interaction of the Wnt signaling cascade with noggin and follistatin. Dev Biol. 1995;172:337–342. [PubMed: 7589812]
Fredieu JR, Cui Y, Maier D. et al. Xwnt-8 and lithium can act upon either dorsal mesodermal or neurectodermal cells to cause a loss of forebrain in Xenopus embryos. Dev Biol. 1997;186:100–114. [PubMed: 9188756]
McGrew LL, Hoppler S, Moon RT. Wnt and FGF pathways cooperatively pattern anteroposterior neural ectoderm in Xenopus. Mech Dev. 1997;69:105–114. [PubMed: 9486534]
Saint-Jeannet JP, He X, Varmus HE. et al. Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a. Proc Natl Acad Sci USA. 1997;94:13713–13718. [PMC free article: PMC28371] [PubMed: 9391091]
Chang C, Hemmati-Brivanlou A. Neural crest induction by Xwnt7B in Xenopus. Dev Biol. 1998;194:129–134. [PubMed: 9473337]
McGrew LL, Takemaru K, Bates R. et al. Direct regulation of the Xenopus engrailed-2 promoter by the Wnt signaling pathway, and a molecular screen for Wnt-responsive genes, confirm a role for Wnt signaling during neural patterning in Xenopus. Mech Dev. 1999;87:21–32. [PubMed: 10495268]
Kazanskaya O, Glinka A, Niehrs C. The role of Xenopus dickkopf1 in prechordal plate specification and neural patterning. Development. 2000;127:4981–4992. [PubMed: 11044411]
Darken RS, Wilson PA. Axis induction by wnt signaling: Target promoter responsiveness regulates competence. Dev Biol. 2001;234:42–54. [PubMed: 11356018]
Domingos PM, Itasaki N, Jones CM. et al. The Wnt/β-Catenin Pathway Posteriorizes Neural Tissue in Xenopus by an Indirect Mechanism Requiring FGF Signaling. Dev Biol. 2001;239:148–160. [PubMed: 11784025]
Gamse JT, Sive H. Early anteroposterior division of the presumptive neurectoderm in Xenopus. Mech Dev. 2001;104:21–36. [PubMed: 11404077]
Hamilton FS, Wheeler GN, Hoppler S. Difference in XTCF-3 dependency accounts for change in response to β-catenin-mediated Wnt signaling in Xenopus blastula. Development. 2001;128:2063–2073. [PubMed: 11493528]
Kiecker C, Niehrs C. A morphogen gradient of Wnt/β-catenin signaling regulates anteroposterior neural patterning in Xenopus. Development. 2001;128:4189–4201. [PubMed: 11684656]
Wheeler GN, Hamilton FS, Hoppler S. Inducible gene expression in transgenic Xenopus embryos. Curr Biol. 2000;10:849–852. [PubMed: 10899005]
Pöpperl H, Schmidt C, Wilson V. et al. Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development. 1997;124:2997–3005. [PubMed: 9247341]
Roeser T, Stein S, Kessel M. Nuclear β-catenin and the development of bilateral symmetry in normal and LiCl-exposed chick embryos. Development. 1999;126:2955–2965. [PubMed: 10357939]
Hoppler S, Brown JD, Moon RT. Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos. Genes Dev. 1996;10:2805–2817. [PubMed: 8946920]
Pierce SB, Kimelman D. Overexpression of Xgsk-3 disrupts anterior ectodermal patterning in Xenopus. Dev Biol. 1996;175:256–264. [PubMed: 8626031]
Glinka A, Wu W, Onichtchouk D. et al. Head induction by simultaneous repression of Bmp and Wnt signaling in Xenopus. Nature. 1997;389:517–519. [PubMed: 9333244]
Leyns L, Bouwmeester T, Kim SH. et al. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell. 1997;88:747–756. [PMC free article: PMC3061830] [PubMed: 9118218]
Wang S, Krinks M, Lin K. et al. Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell. 1997;88:757–766. [PubMed: 9118219]
Deardorff MA, Tan C, Conrad LJ. et al. Frizzled-8 is expressed in the Spemann organizer and plays a role in early morphogenesis. Development. 1998;125:2687–2700. [PubMed: 9636083]
Glinka A, Wu W, Delius H. et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 1998;391:357–362. [PubMed: 9450748]
Hsieh JC, Kodjabachian L, Rebbert ML. et al. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999;398:431–436. [PubMed: 10201374]
Fekany-Lee K, Gonzalez E, Miller-Bertoglio V. et al. The homeobox gene bozozok promotes anterior neuroectoderm formation in zebrafish through negative regulation of BMP2/4 and Wnt pathways. Development. 2000;127:2333–2345. [PubMed: 10804176]
Hashimoto H, Itoh M, Yamanaka Y. et al. Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. Dev Biol. 2000;217:138–152. [PubMed: 10625541]
Shinya M, Eschbach C, Clark M. et al. Zebrafish Dkk1, induced by the pre-MBT Wnt signaling, is secreted from the prechordal plate and patterns the anterior neural plate. Mech Dev. 2000;98:3–17. [PubMed: 11044603]
Itoh K, Tang TL, Neel BG. et al. Specific modulation of ectodermal cell fates in Xenopus embryos by glycogen synthase kinase. Development. 1995;121:3979–3988. [PubMed: 8575298]
Heasman J, Kofron M, Wylie C. β-catenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach. Dev Biol. 2000;222:124–134. [PubMed: 10885751]
Takada S, Stark KL, Shea MJ. et al. Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev. 1994;8:174–189. [PubMed: 8299937]
Yamaguchi TP, Bradley A, McMahon AP. et al. A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development. 1999;126:1211–1223. [PubMed: 10021340]
Galceran J, Farinas I, Depew MJ. et al. Wnt3a-/--like phenotype and limb deficiency in LEF-1-/- TCF-1-/- mice. Genes Dev. 1999;13:709–717. [PMC free article: PMC316557] [PubMed: 10090727]
Pinson KI, Brennan J, Monkley S. et al. An LDL-receptor-related protein mediates Wnt signaling in mice. Nature. 2000;407:535–538. [PubMed: 11029008]
Lekven AC, Thorpe CJ, Waxman JS. et al. Zebrafish wnt8 encodes two wnt8 proteins on a bicistronic transcript and is required for mesoderm and neurectoderm patterning. Dev Cell. 2001;1:103–114. [PubMed: 11703928]
Greco TL, Takada S, Newhouse MM. et al. Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev. 1996;10:313–324. [PubMed: 8595882]
Erter CE, Wilm TP, Basler N. et al. Wnt8 is required in lateral mesendodermal precursors for neural posteriorization in vivo. Development. 2001;128:3571–3583. [PubMed: 11566861]
Hemmati-Brivanlou A, Stewart RM, Harland RM. Region-specific neural induction of an engrailed protein by anterior notochord in Xenopus. Science. 1990;250:800–802. [PubMed: 1978411]
Doniach T, Musci TJ. Induction of anteroposterior neural pattern in Xenopus: evidence for a quantitative mechanism. Mech Dev. 1995;53:403–413. [PubMed: 8645606]
Ang SL, Rossant J. Anterior mesendoderm induces mouse Engrailed genes in explant cultures. Development. 1993;118:139–149. [PubMed: 8375331]
Rowan AM, Stern CD, Storey KG. Axial mesendoderm refines rostrocaudal pattern in the chick nervous system. Development. 1999;126:2921–2934. [PubMed: 10357936]
Bang AG, Papalopulu N, Kintner C. et al. Expression of Pax-3 is initiated in the early neural plate by posteriorizing signals produced by the organizer and by posterior non-axial mesoderm. Development. 1997;124:2075–2085. [PubMed: 9169853]
Muhr J, Jessell TM, Edlund T. Assignment of early caudal identity to neural plate cells by a signal from caudal paraxial mesoderm. Neuron. 1997;19:487–502. [PubMed: 9331343]
Woo K, Fraser SE. Specification of the zebrafish nervous system by nonaxial signals. Science. 1997;277:254–257. [PubMed: 9211857]
Ensini M, Tsuchida TN, Belting HG. et al. The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm. Development. 1998;125:969–982. [PubMed: 9463344]
Bang AG, Papalopulu N, Goulding MD. et al. Expression of Pax-3 in the lateral neural plate is dependent on a Wnt-mediated signal from posterior nonaxial mesoderm. Dev Biol. 1999;212:366–380. [PubMed: 10433827]
De Robertis EM, Larraín J, Oelgeschläger M. et al. The establishment of Spemann's organizer and patterning of the vertebrate embryo. Nat Rev Genet. 2000;1:171–181. [PMC free article: PMC2291143] [PubMed: 11252746]
Niehrs C. Head in the WNT: the molecular nature of Spemann's head organizer. Trends Genet. 1999;15:314–319. [PubMed: 10431193]
Kiecker C, Niehrs C. The role of prechordal mesendoderm in neural patterning. Curr Opin Neurobiol. 2001;11:27–33. [PubMed: 11179869]
Schneider VA, Mercola M. Spatially distinct head and heart inducers within the Xenopus organizer region. Curr Biol. 1999;9:800–809. [PubMed: 10469564]
Pera EM, Kessel M. Patterning of the chick forebrain anlage by the prechordal plate. Development. 1997;124:4153–4162. [PubMed: 9374411]
Kim CH, Oda T, Itoh M. et al. Repressor activity of Headless/TCF-3 is essential for vertebrate head formation. Nature. 2000;407:913–916. [PMC free article: PMC4018833] [PubMed: 11057671]
Heisenberg CP, Houart C, Take-Uchi M. et al. A mutation in the Gsk3-binding domain of zebrafish Masterblind/Axin1 leads to a fate transformation of telencephalon and eyes to diencephalon. Genes Dev. 2001;15:1427–1434. [PMC free article: PMC312705] [PubMed: 11390362]
Mukhopadhyay M, Shtrom S, Rodriguez-Esteban C. et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev Cell. 2001;1:423–434. [PubMed: 11702953]
Pera EM, Wessely O, Li SY. et al. Neural and Head Induction by Insulin-like Growth Factor Signals. Dev Cell. 2001;1:655–665. [PubMed: 11709186]
Marvin MJ, Di Rocco G, Gardiner A. et al. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev. 2001;15:316–327. [PMC free article: PMC312622] [PubMed: 11159912]
Schneider VA, Mercola M. Wnt antagonism initiates cardiogenesis in Xenopus laevis. Genes Dev. 2001;15:304–315. [PMC free article: PMC312618] [PubMed: 11159911]
Tzahor E, Lassar AB. Wnt signals from the neural tube block ectopic cardiogenesis. Genes Dev. 2001;15:255–260. [PMC free article: PMC312627] [PubMed: 11159906]
Tam PP, Steiner KA. Anterior patterning by synergistic activity of the early gastrula organizer and the anterior germ layer tissues of the mouse embryo. Development. 1999;126:5171–5179. [PubMed: 10529433]
Thomas P, Beddington R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr Biol. 1996;6:1487–1496. [PubMed: 8939602]
Beddington RS, Robertson EJ. Axis development and early asymmetry in mammals. Cell. 1999;96:195–209. [PubMed: 9988215]
Perea-Gomez A, Rhinn M, Ang SL. Role of the anterior visceral endoderm in restricting posterior signals in the mouse embryo. Int J Dev Biol. 2001;45:311–320. [PubMed: 11291861]
De Souza FS, Niehrs C. Anterior endoderm and head induction in early vertebrate embryos. Cell Tissue Res. 2000;300:207–217. [PubMed: 10867817]
Kimura C, Yoshinaga K, Tian E. et al. Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev Biol. 2000;225:304–321. [PubMed: 10985852]
Belo JA, Bouwmeester T, Leyns L. et al. Cerberus-like is a secreted factor with neuralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech Dev. 1997;68:45–57. [PubMed: 9431803]
Biben C, Stanley E, Fabri L. et al. Murine cerberus homologue mCer-1: a candidate anterior patterning molecule. Dev Biol. 1998;194:135–151. [PubMed: 9501024]
Shawlot W, Deng JM, Behringer RR. Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. Proc Natl Acad Sci USA. 1998;95:6198–6203. [PMC free article: PMC27625] [PubMed: 9600941]
Pearce JJ, Penny G, Rossant J. A mouse cerberus/Dan-related gene family. Dev Biol. 1999;209:98–110. [PubMed: 10208746]
Simpson EH, Johnson DK, Hunsicker P. et al. The mouse Cer1 (Cerberus related or homologue) gene is not required for anterior pattern formation. Dev Biol. 1999;213:202–206. [PubMed: 10452857]
Belo JA, Bachiller D, Agius E. et al. Cerberus-like is a secreted BMP and nodal antagonist not essential for mouse development. Genesis. 2000;26:265–270. [PubMed: 10748465]
Shawlot W, Min Deng J, Wakamiya M. et al. The cerberus-related gene, Cerr1, is not essential for mouse head formation. Genesis. 2000;26:253–258. [PubMed: 10748463]
Stanley EG, Biben C, Allison J. et al. Targeted insertion of a lacZ reporter gene into the mouse Cer1 locus reveals complex and dynamic expression during embryogenesis. Genesis. 2000;26:259–264. [PubMed: 10748464]
Borges AC, Marques S, Belo JA. The BMP antagonists cerberus-like and noggin do not interact during mouse forebrain development. Int J Dev Biol. 2001;45:441–444. [PubMed: 11330864]
Knoetgen H, Viebahn C, Kessel M. Head induction in the chick by primitive endoderm of mammalian, but not avian origin. Development. 1999;126:815–825. [PubMed: 9895328]
Foley AC, Skromne I, Stern CD. Reconciling different models of forebrain induction and patterning: a dual role for the hypoblast. Development. 2000;127:3839–3854. [PubMed: 10934028]
Knoetgen H, Teichmann U, Wittler L. et al. Anterior neural induction by nodes from rabbits and mice. Dev Biol. 2000;225:370–380. [PubMed: 10985856]
Lemaire L, Roeser T, Izpisua-Belmonte JC. et al. Segregating expression domains of two goosecoid genes during the transition from gastrulation to neurulation in chick embryos. Development. 1997;124:1443–1452. [PubMed: 9108361]
Storey KG, Crossley JM, De Robertis EM. et al. Neural induction and regionalisation in the chick embryo. Development. 1992;114:729–741. [PubMed: 1618139]
Camus A, Davidson BP, Billiards S. et al. The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo. Development. 2000;127:1799–1813. [PubMed: 10751169]
Houart C, Westerfield M, Wilson SW. A small population of anterior cells patterns the forebrain during zebrafish gastrulation. Nature. 1998;391:788–792. [PubMed: 9486648]
Koshida S, Shinya M, Mizuno T. et al. Initial anteroposterior pattern of the zebrafish central nervous system is determined by differential competence of the epiblast. Development. 1998;125:1957–1966. [PubMed: 9550728]
Doniach T. Basic FGF as an inducer of anteroposterior neural pattern. Cell. 1995;83:1067–1070. [PubMed: 8548794]
Mason I. Neural induction: do fibroblast growth factors strike a cord? Curr Biol. 1996;6:672–675. [PubMed: 8793291]
Gavalas A, Krumlauf R. Retinoid signaling and hindbrain patterning. Curr Opin Genet Dev. 2000;10:380–386. [PubMed: 10889064]
Pownall ME, Tucker AS, Slack JM. et al. eFGF, Xcad3 and Hox genes form a molecular pathway that establishes the anteroposterior axis in Xenopus. Development. 1996;122:3881–3892. [PubMed: 9012508]
Mathis L, Kulesa PM, Fraser SE. FGF receptor signaling is required to maintain neural progenitors during Hensen's node progression. Nat Cell Biol. 2001;3:559–566. [PubMed: 11389440]
Krull CE, Krumlauf R. Building from the bottom up. Nat Cell Biol. 2001;3:E138–E139. [PubMed: 11389452]
Heisenberg CP, Brand M, Jiang YJ. et al. Genes involved in forebrain development in the zebrafish, Danio rerio. Development. 1996;123:191–203. [PubMed: 9007240]
Heisenberg CP, Tada M, Rauch G-J. et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature. 2000;405:76–81. [PubMed: 10811221]
Sokol S. A role for Wnts in morpho-genesis and tissue polarity. Nat Cell Biol. 2000;2:E124–E125. [PubMed: 10878822]
Tada M, Smith JC. Xwnt11 is a target of Xenopus Brachyury: regulation of gastrulation movements via Dishevelled, but not through the canonical Wnt pathway. Development. 2000;127:2227–2238. [PubMed: 10769246]
Wallingford JB, Rowning BA, Vogeli KM. et al. Dishevelled controls cell polarity during Xenopus gastrulation. Nature. 2000;405:81–85. [PubMed: 10811222]
Kühl M, Geis K, Sheldahl LC. et al. Antagonistic regulation of convergent extension movements in Xenopus by Wnt/β-catenin and Wnt/Ca2+ signaling. Mech Dev. 2001;106:61–76. [PubMed: 11472835]
Topczewski J, Sepich DS, Myers DC. et al. The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension. Dev Cell. 2001;1:251–264. [PubMed: 11702784]
Wallingford JB, Harland RM. Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. Development. 2001;128:2581–92. [PubMed: 11493574]
Wallingford JB, Vogeli KM, Harland RM. Regulation of convergent extension in Xenopus by Wnt5a and Frizzled-8 is independent of the canonical Wnt pathway. [PMC free article: PMC58733] [PubMed: 11291850]
Bradley L, Sun B, Collins-Racie L. et al. Different activities of the frizzled-related proteins frzb2 and sizzled2 during Xenopus anteroposterior patterning. Dev Biol. 2000;227:118–132. [PubMed: 11076681]
Pera EM, De Robertis EM. A direct screen for secreted proteins in Xenopus embryos identifies distinct activities for the Wnt antagonists Crescent and Frzb-1. Mech Dev. 2000;96:183–195. [PubMed: 10960783]
Parr BA, Shea MJ, Vassileva G. et al. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development. 1993;119:247–261. [PubMed: 8275860]
Bouillet P, Oulad-Abdelghani M, Ward SJ. et al. A new mouse member of the Wnt gene family, mWnt-8, is expressed during early embryogenesis and is ectopically induced by retinoic acid. Mech Dev. 1996;58:141–152. [PubMed: 8887323]
Kim AS, Lowenstein DH, Pleasure SJ. Wnt receptors and Wnt inhibitors are expressed in gradients in the developing telencephalon. Mech Dev. 2001;103:167–172. [PubMed: 11335128]
Patapoutian A, Reichardt LF. Roles of Wnt proteins in neural development and maintenance. Curr Opin Neurobiol. 2000;10:392–399. [PMC free article: PMC4943213] [PubMed: 10851180]
Wilson SW, Rubenstein JL. Induction and dorsoventral patterning of the telencephalon. Neuron. 2000;28:641–651. [PubMed: 11163256]
Rhinn M, Brand M. The midbrain-hindbrain boundary organizer. Curr Opin Neurobiol. 2001;11:34–42. [PubMed: 11179870]
Wurst W, Bally-Cuif L. Neural plate patterning: upstream and downstream of the isthmic organizer. Nat Rev Neurosci. 2001;2:99–108. [PubMed: 11253000]
Galceran J, Miyashita-Lin EM, Devaney E. et al. Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF-1. Development. 2000;127:469–482. [PubMed: 10631168]
Lee SM, Tole S, Grove E. et al. A local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000;127:457–467. [PubMed: 10631167]
Ikeya M, Lee SM, Johnson JE. et al. Wnt signaling required for expansion of neural crest and CNS progenitors. Nature. 1997;389:966–970. [PubMed: 9353119]
Dorsky RI, Moon RT, Raible DW. Control of neural crest cell fate by the Wnt signaling pathway. Nature. 1998;396:370–373. [PubMed: 9845073]
Deardorff MA, Tan C, Saint-Jeannet JP. et al. A role for frizzled 3 in neural crest development. Development. 2001;128:3655–3663. [PubMed: 11585792]
Tan C, Deardorff MA, Saint-Jeannet JP. et al. Kermit, a frizzled interacting protein, regulates frizzled 3 signaling in neural crest development. Development. 2001;128:3665–3674. [PubMed: 11585793]
LaBonne C, Bronner-Fraser M. Molecular mechanisms of neural crest formation. Annu Rev Cell Dev Biol. 1999;15:81–112. [PubMed: 10611958]
Köntges G, Lumsden A. Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development. 1996;122:3229–3242. [PubMed: 8898235]
Krull CE. Segmental organization of neural crest migration. Mech Dev. 2001;105:37–45. [PubMed: 11429280]
Wilkie AO, Morriss-Kay GM. Genetics of craniofacial development and malformation. Nat Rev Genet. 2001;2:458–468. [PubMed: 11389462]
Wolda SL, Moody CJ, Moon RT. Overlapping expression of Xwnt-3A and Xwnt-1 in neural tissue of Xenopus laevis embryos. Dev Biol. 1993;155:46–57. [PubMed: 8416844]
Cui Y, Brown JD, Moon RT. et al. Xwnt-8tr a maternally expressed Xenopus Wnt gene with a potential role in establishing the dorsoventral axis. Development. 1995;121:2177–2186. [PubMed: 7635061]
Landesman Y, Sokol SY. Xwnt-2b is a novel axis-inducing Xenopus Wnt, which is expressed in embryonic brain. Mech Dev. 1997;63:199–209. [PubMed: 9203142]
Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science. 1996;274:1109–1115. [PubMed: 8895453]
Saxén L. Neural induction. Int J Dev Biol. 1989;33:21–48. [PubMed: 2562048]
Zakin LD, Mazan S, Maury M. et al. Structure and expression of Wnt13, a novel mouse Wnt2 related gene. Mech Dev. 1998;73:107–116. [PubMed: 9545553]
Liu P, Wakamiya M, Shea MJ. et al. Requirement for Wnt3 in vertebrate axis formation. Nat Genet. 1999;22:361–365. [PubMed: 10431240]
Moon RT, Campbell RM, Christian JL. et al. Xwnt-5A: a maternal Wnt that affects morphogenetic movements after overexpression in embryos of Xenopus laevis. Development. 1993;119:97–111. [PubMed: 8275867]
Kuiken GA, Bertens PJ, Peterson-Maduro J. et al. The promoter of the Xwnt-5C gene contains octamer and AP-2 motifs functional in Xenopus embryos. Nucleic Acids Res. 1994;22:1675–1680. [PMC free article: PMC308048] [PubMed: 8202371]
Krauss S, Korzh V, Fjose A. et al. Expression of four zebrafish wnt-related genes during embryogenesis. Development. 1992;116:249–259. [PubMed: 1483391]
Wolda SL, Moon RT. Cloning and developmental expression in Xenopus laevis of seven additional members of the Wnt family. Oncogene. 1992;7:1941–1947. [PubMed: 1408135]
Hume CR, Dodd J. Cwnt-8C: a novel Wnt gene with a potential role in primitive streak formation and hindbrain organization. Development. 1993;119:1147–1160. [PubMed: 7916678]
Eisenberg CA, Gourdie RG, Eisenberg LM. Wnt-11 is expressed in early avian mesoderm and required for the differentiation of the quail mesoderm cell line QCE-6. Development. 1997;124:525–536. [PubMed: 9053328]
Ku M, Melton DA. Xwnt-11: a maternally expressed Xenopus wnt gene. Development. 1993;119:1161–1173. [PubMed: 8306880]
Heisenberg CP, Tada M, Rauch GJ. et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature. 2000;405:76–81. [PubMed: 10811221]
Sasai Y, Lu B, Steinbeisser H. et al. Xenopus chordin: a novel dorsalizing factor activated by organizer- specific homeobox genes. Cell. 1994;79:779–790. [PMC free article: PMC3082463] [PubMed: 8001117]
Piccolo S, Sasai Y, Lu B. et al. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell. 1996;86:589–598. [PMC free article: PMC3070603] [PubMed: 8752213]
Hemmati-Brivanlou A, Kelly OG, Melton DA. Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell. 1994;77:283–295. [PubMed: 8168135]
Fainsod A, Deissler K, Yelin R. et al. The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4. Mech Dev. 1997;63:39–50. [PubMed: 9178255]
Okabayashi K, Shoji H, Onuma Y. et al. cDNA cloning and distribution of the Xenopus follistatinrelated protein. Biochem Biophys Res Commun. 1999;254:42–48. [PubMed: 9920730]
Smith WC, Harland RM. Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell. 1992;70:829–840. [PubMed: 1339313]
Zimmerman LB, De Jesus-Escobar JM, Harland RM. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell. 1996;86:599–606. [PubMed: 8752214]
Bouwmeester T, Kim S, Sasai Y. et al. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer. Nature. 1996;382:595–601. [PubMed: 8757128]
Piccolo S, Agius E, Leyns L. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature. 1999;397:707–710. [PMC free article: PMC2323273] [PubMed: 10067895]
Cheng AM, Thisse B, Thisse C. et al. The lefty-related factor Xatv acts as a feedback inhibitor of nodal signaling in mesoderm induction and L-R axis development in Xenopus. Development. 2000;127:1049–1061. [PubMed: 10662644]
Hollemann T, Chen Y, Grunz H. et al. Regionalized metabolic activity establishes boundaries of retinoic acid signaling. EMBO J. 1998;17:7361–7372. [PMC free article: PMC1171081] [PubMed: 9857192]
Gilbert SF. Developmental Biology6th ed. Sinauer Associates, Inc. Publishers,2000. Sunderland, MA.
Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6025


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...