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PubMed2001

The homeobox genes vox and vent are redundant repressors of dorsal fates in zebrafish.

Ventralizing transcriptional repressors in the Vox/Vent family have been proposed to be important regulators of dorsoventral patterning in the early embryo. While the zebrafish genes vox (vega1) and vent (vega2) both have ventralizing activity in overexpression assays, loss-of-function studies are needed to determine whether these genes have distinct or redundant functions in dorsoventral patterning and to provide critical tests of the proposed regulatory interactions among vox, vent and other genes that act to establish the dorsoventral axis. We show that vox and vent are redundant repressors of dorsal fates in zebrafish. Mutants that lack vox function have little or no dorsoventral patterning defect, and inactivation of either vox or vent by injection of antisense morpholino oligonucleotides has little or no effect on the embryo. In contrast, embryos that lack both vox and vent function have a dorsalized phenotype. Expression of dorsal mesodermal genes, including chordin, goosecoid and bozozok, is strongly expanded in embryos that lack vox and vent function, indicating that the redundant action of vox and vent is required to restrict dorsal genes to their appropriate territories. Our genetic analysis indicates that the dorsalizing transcription factor Bozozok promotes dorsal fates indirectly, by antagonizing the expression of vox and vent. In turn, vox and vent repress chordin expression, restricting its function as an antagonist of ventral fates to the dorsal side of the embryo. Our results support a model in which BMP signaling induces the expression of ventral genes, while vox and vent act redundantly to prevent the expression of chordin, goosecoid and other dorsal genes in the lateral and ventral mesendoderm.

Animals↗

PubMed2000

Two novel nodal-related genes initiate early inductive events in Xenopus Nieuwkoop center.

In vertebrates, Nodal-related protein plays crucial roles in mesoderm and endoderm induction. Here we describe two novel Xenopus nodal-related genes, Xnr5 and Xnr6, which are first zygotically expressed at the mid-blastula transition, in the dorsal-vegetal region including the Nieuwkoop center. Xnr5 and Xnr6 were isolated by expression screening of a library enriched with immediate-early-type transcripts, and are strong inducers of both mesoderm and endoderm. They also induce the other nodal-related genes in the animal cap. In embryos, cerberus-short (nodal-specific inhibitor) can inhibit Xnr1 and Xnr2 express to the same extent goosecoid, but not Xnr5 and Xnr6 transcription. Xnr5 and Xnr6 are regulated completely cell autonomously, differently from other Xnrs in the cell-dissociated embryos. The expression of Xnr5 and Xnr6 is regulated by maternal VegT and (beta)-catenin, but does not require TGF-(beta) signaling. Therefore, expression of Xnr5 and Xnr6 is controlled by different mechanisms from other Xnr family genes.

Amino Acid Sequence↗

PubMed1997

XBMP-1B (Xtld), a Xenopus homolog of dorso-ventral polarity gene in Drosophila, modifies tissue phenotypes of ventral explants.

Previously we have isolated a Xenopus cDNA homolog of bone morphogenetic protein-1 (XBMP-1A). In the present report we describe a new cDNA clone called XBMP-1B (or Xtld) from a Xenopus embryonic library. Sequence analysis indicates that these two clones share an indentical N-terminal sequence, including a region of metalloprotease domain, three copies of a repeat first found in complement proteins C1r/s and an epidermal growth factor (EGF)-like sequence. XBMP-1B protein has an additional copy of an EGF-like sequence followed by two copies of complement 1 r/s repeat in the C-terminus. The overall protein structure predicted from the XBMP-1B sequence reveals that it encodes a protein homologous to Drosophila tolloid. Three XBMP-1 transcripts (2.9, 5.2 and 6.6 kb) were detected by northern blot analysis. However, the 2.9 kb transcript hybridized specifically with XBMP-1A and the 5.2 and 6.6 kb transcripts hybridized with XBMP-1B. In Drosophila, a major function of tolloid is to augment the activity of the decapentaplegic gene product, a close relative of tumor growth factor (TGF)-beta superfamily members, BMP-2/4. Although XBMP-1 and XBMP-4 are detected in various adult tissues of Xenopus, the expression pattern of these two genes was not tightly correlated. In the embryo, the expression of XBMP-1 increased gradually from the morula to the swimming tadpole stages. Injection of XBMP-1B RNA into the ventral blastomeres at the 4-cell stage caused an elongation of the ventral marginal zone explants and converted globin-positive blood cells to mesenchymal and muscle tissues at later stages. It was shown that XBMP-1A was less active and a 1A mutant lacking the signal sequence was inactive. Further studies revealed that injection of XBMP-1B RNA into the ventral marginal zone induced up-regulation of dorsal marginal zone markers, such as goosecoid and chordin, at the gastrulation stage. These data indicate that XBMP-1 may have a role in determining dorso-ventral patterning in Xenopus, but in a different way from the dpp/tolloid system demonstrated in Drosophila.

Amino Acid Sequence↗

PubMed2006

Sonic hedgehog is essential for first pharyngeal arch development.

The secreted protein sonic hedgehog (Shh) is essential for normal development of many organs. Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches. To investigate the role of Shh signaling in early pharyngeal arch development, we analyzed Shh mutant embryos using molecular markers and found that the first pharyngeal arch (PA1) was specifically hypoplastic and fused in the midline, and remaining arches were well formed at embryonic day (E) 9.5. Molecular analyses using specific markers suggested that the growth of the maxillary arch and proximal mandibular arch was severely defective in Shh-null PA1, whereas the distal mandibular arch was less affected. TUNEL assay revealed an increase in the number of apoptotic signals in PA1 of Shh mutant embryos. Ectodermal expression of fibroblast growth factor (Fgf)-8, a cell survival factor for pharyngeal arch mesenchyme, was down-regulated in the PA1 of Shh mutants. Consistent with this observation, downstream transcriptional targets of Fgf8 signaling in neural crest-derived mesenchyme, including Barx1, goosecoid, and Dlx2, were also down-regulated in Shh-null PA1. These results demonstrate that epithelial-mesenchymal signaling and transcriptional events coordinated by Shh, partly via Fgf8, is essential for cell survival and tissue outgrowth of the developing PA1.

Animals↗

PubMed2005

Role of Fyn kinase in signaling associated with epiboly during zebrafish development.

The function of Fyn kinase during zebrafish development through the blastula stage was investigated through the use of dominant-negative constructs designed to suppress the function of zebrafish c-Fyn. Microinjection of SH2 domain-containing fusion protein or mRNA encoding the mutated, catalytically inactive Fyn at 45 min post-insemination had no significant effect during cleavage and did not inhibit formation of the yolk syncitial layer. Smoothing of the enveloping cell layer at the midblastula transition occurred normally and expression of bon/mixer and mezzo, zygotic transcription factors indicated that activation of the zygotic genome did occur. Signaling pathways involved with axis determination such as beta-catenin, activin, and nodal appeared to function normally as evidenced by expression of boz, goosecoid, and mezzo. However, while formation of the yolk syncitial layer was normal, the marginal blastomeres failed to migrate toward the vegetal pole and epiboly did not occur, a phenotype similar but distinct from that resulting from suppression of c-Yes kinase. The block to development was prevented by co-injection of c-Fyn mRNA with the dominant-negative construct indicating that it was a specific effect. Injection of the dominant-negative mRNA into individual blastomeres indicated that the effect was exerted on the intrinsic ability of the individual blastomeres to respond to signals directing epiboly and not on the signals themselves. Analysis of the pattern of calcium signaling in experimental and control embryos demonstrated that the elevated [Ca2+]i characteristic of the marginal blastomeres was suppressed. Together, these observations indicate that Fyn kinase plays an important role in epiboly, possibly through its effects in calcium signaling.

Animals↗

PubMed1998

Determination of the zebrafish forebrain: induction and patterning.

We report an analysis of forebrain determination and patterning in the zebrafish Danio rerio. In order to study these events, we isolated zebrafish homologs of two neural markers, odd-paired-like (opl), which encodes a zinc finger protein, and fkh5, which encodes a forkhead domain protein. At mid-gastrula, expression of these genes defines a very early pattern in the presumptive neurectoderm, with opl later expressed in the telencephalon, and fkh5 in the diencephalon and more posterior neurectoderm. Using in vitro explant assays, we show that forebrain induction has occurred even earlier, by the onset of gastrulation (shield stage). Signaling from the early gastrula shield, previously shown to be an organizing center, is sufficient for activation of opl expression in vitro. In order to determine whether the organizer is required for opl regulation, we removed from late blastula stage embryos either the presumptive prechordal plate, marked by goosecoid (gsc) expression, or the entire organizer, marked by chordin (chd) expression. opl was correctly expressed after removal of the presumptive prechordal plate and consistently, opl was correctly expressed in one-eyed pinhead (oep) mutant embryos, where the prechordal plate fails to form. However, after removal of the entire organizer, no opl expression was observed, indicating that this region is crucial for forebrain induction. We further show that continued organizer function is required for forebrain induction, since beads of BMP4, which promotes ventral fates, also prevented opl expression when implanted during gastrulation. Our data show that forebrain specification begins early during gastrulation, and that a wide area of dorsal mesendoderm is required for its patterning.

Amino Acid Sequence↗

PubMed2004

Ectopic expression and knockdown of a zebrafish sox21 reveal its role as a transcriptional repressor in early development.

Sox proteins are DNA-binding proteins belonging to the HMG box superfamily and they play key roles in animal embryonic development. Zebrafish Sox21a is part of group B Sox proteins and its chicken and mouse orthologs have been described as transcriptional repressor and activator, respectively, in two different target gene contexts. Zebrafish sox21a is present as a maternal transcript in the oocyte and is mainly expressed at the developing midbrain-hindbrain boundary from the onset of neurulation. In order to understand its role in vivo, we ectopically expressed sox21a by microinjection. Ectopic expression of full length sox21a leads to dorsalization of the embryos. A subset of the dorsalized embryos shows a partial axis splitting, and hence an ectopic neural tube, as an additional phenotype. At gastrulation, injected embryos show expansion of the expression domains of organizer-specific genes, such as chordin and goosecoid. Molecular markers used in somitogenesis highlight that sox21a-injected embryos have shortened AP axis, undulating axial structures, enlarged or even radialized paraxial territory. The developmental abnormalities caused by ectopic expression of sox21a are suggestive of defects in convergence-extension morphogenetic movements. Antisense morpholino oligonucleotides, designed to functionally knockdown sox21a, cause ventralization of the embryos. Moreover, gain-of-function experiments with chimeric constructs, where Sox21a DNA-binding domain is fused to a transcriptional activator (VP16) or repressor (EnR) domain, suggests that zebrafish Sox21a acts as a repressor in dorso-ventral patterning.

Animals↗

PubMed2001

The pitx2 homeobox protein is required early for endoderm formation and nodal signaling. .

Nodal and Nodal-related factors play fundamental roles in a number of developmental processes, including mesoderm and endoderm formation, patterning of the anterior neural plate, and determination of bilateral asymmetry in vertebrates. pitx2, a paired-like homeobox gene, has been proposed to act downstream of Nodal in the gene cascade providing left-right cues to the developing organs. Here, we report that pitx2 is required early in the Nodal signaling pathway for specification of the endodermal and mesodermal germ layers. We found that pitx2 is expressed very early during Xenopus and zebrafish development and in many regions where Nodal signaling is required, including the presumptive mesoderm and endoderm at the blastula and gastrula stages and the prechordal mesoderm at later stages. In Xenopus embryos, overexpression of pitx2 caused ectopic expression of goosecoid and sox-17 and interfered with mesoderm formation. Overexpression of pitx2 in Xenopus animal cap explants partially mimics the effects of Nodal overexpression, suggesting that pitx2 is a mediator of Nodal signaling during specification of the endoderm and prechordal plate, but not during mesoderm induction. We further demonstrate that pitx2 is induced by Nodal signaling in Xenopus animal caps and that the early expression of zebrafish pitx2 is absent when the Nodal signaling pathway is inactive. Inhibition of pitx2 function using a chimeric EnR-pitx2 blocked specification of the mesoderm and endoderm and caused severe embryonic defects resembling those seen when Nodal signaling is inhibited. Following inhibition of pitx2 function, the fate of ventral vegetal blastomeres was shifted from an endodermal to a more mesodermal fate, an effect that was reversed by wild-type pitx2. Finally, we show that inhibition of pitx2 function interferes with the response of cells to Nodal signaling. Our results provide direct evidence that pitx2 function is required for normal specification of the endodermal and mesodermal germ layers.

Amino Acid Sequence↗

PubMed1995

A homeobox gene involved in node, notochord and neural plate formation of chick embryos.

We have isolated a chicken cDNA clone, Cnot, resembling in sequence and expression pattern the Xenopus homeobox gene Xnot. The major, early transcription domains of Cnot are the node, the notochord and prenodal and postnodal neural plate caudal from the prospective hindbrain level. All these cell populations appear to be descendants of the Cnot-expressing cells of the node, suggesting a cell lineage relationship. After the onset of somitogenesis, a second, independent expression domain appears in the neural folds at the prospective mid- and forebrain levels, and further transcripts are found in the epiphysis, the ventral diencephalon, the preoral gut and the limb buds. Transplantation of nodes from extended streak embryos leads to the formation of ectopic notochords, which express Cnot in the typical, cranially decreasing gradient. Transplantation of young nodes to young hosts has previously been described to induce secondary embryos. We observed that secondary chick embryos express Cnot in node derived, notochord-like structures and in the anterior neural plate, similar to the domains seen in primary embryos. However, expression was absent from the posterior neural plate, which in the induction experiments is excluded from the node lineage. This finding corroborates our initial conclusion about a cell lineage relationship between node, notochord, and neural plate defined by Cnot expression. The midline mesoderm of vertebrate embryos consists of two tissues, the prechordal mesoderm and the notochord. The anterior notochord, the head process, may represent an intermediate form. The transition from prechordal to chordal mesoderm can be followed by the expression of the two marker homeobox genes goosecoid and Cnot, first in the primitive streak, and then in the head process. We suggest that expression of goosecoid or Cnot is involved in the specification of a prechordal or notochordal identity, respectively. A transition from goosecoid to Cnot expression may proceed, while cells are still in the epiblast, but not after becoming mesodermal. A molecular coding of axial positions in the midline mesoderm may occur by specific homeobox genes, similar to the situation in the neural tube and the somitic mesoderm.

Amino Acid Sequence↗

PubMed1998

Patterns of gene expression in the core of Spemann's organizer and activin-treated ectoderm in Cynops pyrrhogaster.

The presumptive pharyngeal endoderm region of the Cynops early gastrula induces head or trunk-tail structures in sandwich culture. Activin-treated ectoderm can mimic this phenomenon at least at the histological level. The patterns of expression of organizer-specific genes were examined to compare these two inductive materials at the molecular level. A chordin cDNA clone from Cynops pyrrhogaster (Cychd) was isolated by reverse transcription-polymerase chain reaction (RT-PCR). Cychd mRNA was first detected in the presumptive pharyngeal endoderm and prechordal plate regions of stage 11 embryos, and was expressed continuously until stage 20. The spatiotemporal expression pattern of Cychd was similar to that of Xenopus chordin. The patterns of expression of organizer-related genes in the pharyngeal endoderm and activin-treated ectoderm were compared by RT-PCR analysis. Expression of Cychd in these two materials peaked at the time when they can induce head structures in sandwich culture. Expression of fork head and goosecoid did not change in the presumptive pharyngeal endoderm over this period. Cychd may play a key role in head formation in the Cynops embryo.

Activins↗

PubMed1997

Siamois is required for formation of Spemann's organizer.

Spemann's organizer develops in response to dorsal determinants that act via maternal components of the wnt pathway. The function of siamois, a wnt-inducible homeobox gene, in Spemann's organizer development was examined by fusion of defined transcriptional regulatory domains to the siamois homeodomain. Similar to native siamois, a VP16 activator fusion induced axis formation, indicating that siamois functions as a transcriptional activator in axis induction. Fusion of the engrailed repressor generated a dominant inhibitor that blocked axis induction by Xwnt8, beta-catenin, and siamois, and repressed wnt activation of the goosecoid promoter. Dorsal injection of the engrailed-siamois fusion resulted in complete inhibition of dorsal development and organizer gene expression, an effect rescued by siamois, but not by Xwnt8 or beta-catenin. Thus, as a zygotic mediator of maternal dorsal signals, siamois function is required for development of Spemann's organizer.

Animals↗

PubMed1994

Spatially regulated expression of three receptor tyrosine kinase genes during gastrulation in the zebrafish.

We describe the isolation and early developmental expression of three novel zebrafish genes (rtk1-3) that encode members of the eph family of receptor tyrosine kinases. At the onset of gastrulation, rtk1 is expressed in the shield region corresponding to the future dorsal side of the embryo. As gastrulation proceeds, both rtk1 and rtk2 are expressed within the axial hypoblast along the entire axis of the embryo. After the gastrula stage is complete, expression of both genes is maintained in precursor cells of the notochord in the tail bud but is downregulated in other regions of the axial hypoblast, rtk3 is expressed in anterior axial hypoblast including the 'pillow' at the anterior tip of the hypoblast and in paraxial tissue in posterior regions of the embryo. We show that the precise spatial regulation of expression of rtk genes, ntl and goosecoid along the anteroposterior axis is maintained in embryos that have no dorsoventral axis. This indicates that the mechanisms that regulate gene expression along the anteroposterior and dorsoventral axes of the hypoblast may be independent.

Amino Acid Sequence↗

PubMed2004

Functional and hierarchical interactions among zebrafish vox/vent homeobox genes.

The vertebrate Vox/Vent family of transcription factors plays a crucial role in the establishment of the dorsoventral (DV) axis, by repressing organizer genes such as bozozok/dharma, goosecoid, and chordino. In Danio rerio (zebrafish), members of the vox/vent gene family (vox/vega1, vent/vega2, and ved) are thought to share expression patterns and functional properties. Bringing novel insights in the differential activity of the zebrafish vox/vent genes, we propose a critical role for the ved gene in DV patterning of vertebrate embryos. ved is not only expressed as a maternal gene, but it also appears to function as a repressor of dorsal factors involved in organizer formation. At early- and mid-gastrula stage, ved appears to be finely controlled by antagonist crosstalks in a complex regulatory network, involving gradients of bone morphogenetic protein (BMP) activity, dorsal factors, and vox/vent family members. We show that ved transcripts are ventrally restricted by BMP factors such as bmp2b, bmp7, smad5, and alk8, and by dorsal factors (chd and gsc). Alteration of ved expression in both vox and vent deletion mutants and vox and vent mRNAs-injected embryos, suggests that vox and vent function downstream of BMP signaling to negatively regulate ved expression. This inhibitory role is emphasized by a vox and vent redundant activity, compared with single gene effects.

Amino Acid Sequence↗

PubMed1996

A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo.

The engrailed homeoprotein is a dominantly acting or 'active' transcriptional repressor both in cultured cells and in vivo. When retargeted via a homeodomain swap to the endogenous fushi tarazu gene (ftz), it actively represses it, resulting in a ftz mutant phenocopy. We have mapped functional regions of engrailed using this in vivo repression assay. In addition to a region containing an active repression domain identified in cell culture assays (K. Han and J. L. Manley (1993) EMBO J. 12, 2723-2733), we find that two evolutionarily conserved regions contribute to activity. The one of these that does not flank the HD is particularly crucial to repression activity in vivo. We find that this domain is present not only in all engrailed-class homeoproteins but also in all known members of several other classes, including goosecoid, Nk1, Nk2 and msh. Thus engrailed's active repression function in vivo is dependent on a highly conserved interaction that was established early in the evolution of the homeobox gene superfamily. We further show using rescue transgenes that the widely conserved in vivo repression domain is required for the normal function of engrailed in the embryo.

Amino Acid Sequence↗

PubMed1993

Competence prepattern in the animal hemisphere of the 8-cell-stage Xenopus embryo.

Activins are known to be potentially important regulators in Xenopus developmental processes. It has been shown that activins exist maternally in the egg and can induce mesodermal tissues in blastula animal cap explants. However, the blastula ectoderm is known to possess a predisposed local response pattern to activin, and the process of the prepatterning is not understood. We isolated animal hemispheres from late 8-cell-stage embryos and treated them briefly with activin A. Expression of the muscle-specific actin gene was induced after a 30-min activin treatment, even when it was followed by treatment with follistatin, an activin-specific binding protein. This suggests that the animal-half blastomeres become competent to activin A before the 16-cell stage. In the normal embryo, the 8-cell-stage animal dorsal blastomeres populate neural ectoderm and most of the dorsal lip of the gastrula blastopore, the region of Spemann's organizer, and are the major progenitor for dorsal mesodermal tissues. When the dorsal and ventral animal-half blastomeres of the 8-cell stage were isolated and treated with activin independently, significant differences in tissue differentiation were observed. Dorsal blastomeres gave rise to trunk and tail structures containing dorsal mesoderm, whereas the ventral blastomere explants formed spheres containing solely ventral mesoderm. Further, both muscle actin transcription and goosecoid transcription were induced primarily in dorsal blastomeres. Our results suggest that a competence prepattern of response to activin exists as early as the 8-cell stage.

Activins↗

PubMed1998

Function of zebrafish beta-catenin and TCF-3 in dorsoventral patterning.

We report the molecular cloning and expression of the zebrafish tcf-3 homologue and study its function and that of zebrafish betacat in dorsoventral patterning. Overexpression of mutant zTcf-3 products and Cadherin leads to a reduction in the expression of the dorsal-specific genes goosecoid and chording at the blastula stages, indicating a conserved role for betacat and tcf-3 in zebrafish dorsal axis induction. Later during gastrulation, overexpression of these same products leads to the ectopic expression of dorsal-specific genes in the marginal zone and the induction of ectopic axes, suggesting an additional role for betacat and Tcf-3 at these later stages in the repression of dorsal fates.

Amino Acid Sequence↗

PubMed2000

Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice.

Most of the bone and cartilage in the craniofacial region is derived from cephalic neural crest cells, which undergo three primary developmental events: migration from the rhombomeric neuroectoderm to the pharyngeal arches, proliferation as the ectomesenchyme within the arches, and differentiation into terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can lead to craniofacial malformation. We have previously shown that the G-protein-coupled endothelin-A receptor (ET(A)) is expressed in the neural crest-derived ectomesenchyme, whereas the cognate ligand for ET(A), endothelin-1 (ET-1), is expressed in arch epithelium and the paraxial mesoderm-derived arch core; absence of either ET(A) or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neural crest development is disrupted in ET(A)-deficient embryos. We find that, while neural crest cell migration in the head of ET(A)(-/-) embryos appears normal, expression of a number of transcription factors in the arch ectomesenchymal cells is either absent or significantly reduced. These ET(A)-dependent factors include the transcription factors goosecoid, Dlx-2, Dlx-3, dHAND, eHAND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the size of the arches in E10.5 to E11.5 ET(A)(-/-) embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ET(A) signaling in ectomesenchymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesenchyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells, apoptosis. In particular, this developmental pathway appears distinct from the pathway that includes UFD1L, implicated as a causative gene in CATCH 22 patients, and suggests parallel complementary pathways mediating craniofacial development.

Animals↗

PubMed2004

The involvement of Frodo in TCF-dependent signaling and neural tissue development.

Frodo is a novel conserved regulator of Wnt signaling that has been identified by its association with Dishevelled, an intracellular component of Wnt signal transduction. To understand further how Frodo functions, we have analyzed its role in neural development using specific morpholino antisense oligonucleotides. We show that Frodo and the closely related Dapper synergistically regulate head development and morphogenesis. Both genes were cell-autonomously required for neural tissue formation, as defined by the pan-neural markers sox2 and nrp1. By contrast, beta-catenin was not required for pan-neural marker expression, but was involved in the control of the anteroposterior patterning. In the mesoderm, Frodo and Dapper were essential for the expression of the organizer genes chordin, cerberus and Xnr3, but they were not necessary for the expression of siamois and goosecoid, established targets of beta-catenin signaling. Embryos depleted of either gene showed a decreased transcriptional response to TCF3-VP16, a beta-catenin-independent transcriptional activator. Whereas the C terminus of Frodo binds Dishevelled, we demonstrate that the conserved N-terminal domain associates with TCF3. Based on these observations, we propose that Frodo and Dapper link Dsh and TCF to regulate Wnt target genes in a pathway parallel to that of beta-catenin.

Adaptor Proteins, Signal Transducing↗