Overexpression of cadherins and underexpression of ?-catenin inhibit dorsal mesoderm induction in early Xenopus embryos

Heasman, Janet; Crawford, Aaron W.; Goldstone, Kim; Garner-Hamrick, Peggy A.; Gumbiner, Barry M.; McCrea, Pierre D.; Kintner, Chris; Yoshida-Noro, Chikako; Wylie, Chris

doi:10.1016/0092-8674(94)90069-8

Cited by 627 publications

(436 citation statements)

References 52 publications

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“…22 However, it should be pointed out that in contrast to X. tropicalis (used in our study), X. laevis has two RIPK4 genes and the morpholinos used by Huang et al 22 contains mismatches with the xRipk4-b gene, possibly explaining the absence of a gastrulation or cloacal phenotype in this study compared with ours. In line with the Huang et al 23 study, we found that RIPK4 depletion in X. tropicalis narrowed the expression domain of chordin, a dorsal organizer gene. This is consistent with a slight reduction in maternal Wnt/β-catenin signaling.…”

Section: G H and I)supporting

confidence: 91%

“…22 However, it is important to note that embryos that are completely ventralized by depletion of maternal β-catenin do still gastrulate. 23 Hence, we believe that the strong gastrulation phenotype we observe cannot be attributed to aberrant Wnt signaling alone or cell fate changes in general and is the result of aberrant morphogenetic movements.…”

Section: G H and I)mentioning

confidence: 80%

“…This is consistent with a slight reduction in maternal Wnt/β-catenin signaling. Because embryos depleted for maternal β-catenin do gastrulate normally, 23 defective β-catenin signaling cannot explain the gastrulation defect caused by xRIPK4 depletion. Likewise, keratinocyte-specific β-catenin deletion did not result in epidermal and oral fusions.…”

Section: G H and I)mentioning

confidence: 99%

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A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

et al. 2014

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Receptor-interacting protein kinase 4 (RIPK4)-deficient mice have epidermal defects and fusion of all external orifices. These are similar to Bartsocas-Papas syndrome and popliteal pterygium syndrome (PPS) in humans, for which causative mutations have been documented in the RIPK4 and IRF6 (interferon regulatory factor 6) gene, respectively. Although genetically distinct, these syndromes share the anomalies of marked pterygia, syndactyly, clefting and hypoplastic genitalia. Despite the strong resemblance of these two syndromes, no molecular connection between the transcription factor IRF6 and the kinase RIPK4 was known and the mechanism underlying the phenotype was unclear. Here we describe that RIPK4 deficiency in mice causes epithelial fusions associated with abnormal periderm development and aberrant ectopic localization of E-cadherin on the apical membrane of the outer peridermal cell layers. In Xenopus, RIPK4 depletion causes the absence of ectodermal epiboly and concomitant gastrulation defects that phenocopy ectopic expression of dominant-negative IRF6. We found that IRF6 controls RIPK4 expression and that wild-type, but not kinase-dead, RIPK4 can complement the gastrulation defect in Xenopus caused by IRF6 malfunctioning. In contrast to the mouse, we observed only minor effects on cadherin membrane expression in Xenopus RIPK4 morphants. However, gastrulation defects were associated with a virtual absence of cortical actin in the ectodermal cells that face the blastocoel cavity and this was phenocopied in embryos expressing dominant-negative IRF6. A role for RIPK4 in actin cytoskeleton organization was also revealed in mouse epidermis and in human epithelial HaCaT cells. In conclusion, we showed that in mice RIPK4 is implicated in cortical actin organization and in E-cadherin localization or function, which can explain the characteristic epithelial fusions observed in PPSs. In addition, we provide a novel molecular link between IRF6 and RIPK4 that unifies the different PPSs to a common molecular pathway.

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Section: G H and I)supporting

confidence: 91%

Section: G H and I)mentioning

confidence: 80%

Section: G H and I)mentioning

confidence: 99%

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A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

et al. 2014

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“…Lack of mesodermal structures suggests an interference with early inductive signals. Indeed, this phenotype is very similar to dorsal organizer suppression by Axin, dominantnegative TCF, as well as depletion of b-Catenin on the dorsal side (Heasman et al, 1994;reviewed in Sokol, 1999). In addition, the suppression of dorsal structures by CHOP was reversed after injection of siamois RNA (8-16 pg), a downstream Wnt target gene required for organizer formation (Figure 1c).…”

Section: Chop Inhibits Dorsal Embryonic Structures In Xenopus Embryosmentioning

confidence: 83%

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

et al. 2006

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CHOP (GADD153) is a protein of the C/EBP family of transcriptional regulators, which dimerizes with other C/EBP members and changes their DNA-binding and transactivation properties. It induces growth arrest and apoptosis after endoplasmatic reticulum stress or DNA damage. CHOP is also expressed during early embryogenesis and upregulated in tumour tissues with defective Wnt signals. We report here that CHOP functions as a specific inhibitor of Wnt/T-cell factor (TCF) signalling. CHOP inhibits TCF-dependent transcription in human embryonic and colon cancer cell lines. Injection of CHOP mRNA into early Xenopus laevis embryos suppresses dorsal organizer formation and inhibits secondary axis formation and TCF-dependent transcription in response to Wnt-8, Dishevelled, b-Catenin and TCF-VP16. In embryos and human cells, this inhibition depends on the N-terminal transactivation domain of CHOP, whereas the C-terminal dimerization domain is dispensable. CHOP binds to TCF factors, thereby preventing the binding of TCF to its DNA recognition site. Our findings demonstrate a novel function of CHOP as a Wnt repressor.

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“…In adherens junctions, b-catenin and plakoglobin independently associate with the cytoplasmic domain of adhesion receptors of the cadherin family, linking them to the actin cytoskeleton via an association with a-catenin (Takeichi, 1990;Geiger and Ayalon, 1992;Kemler, 1993;Adams and Nelson, 1998;Takeichi, 1995). In addition to this structural role in cell adhesion, bcatenin and its Drosophila homolog, armadillo, are key components of the wg/wnt-signaling pathway (Peifer and Wieschaus, 1990;Peifer et al, 1993;Wodarz and Nusse, 1998) that regulates developmental processes, including speci®cation of the anterior-posterior segment polarity in Drosophila (Peifer et al, 1993), and axis determination in developing Xenopus embryos (Heasman et al, 1994). Signaling by b-catenin is carried out mainly by the nuclear pool of the protein, and recruitment of this protein to adherens junctions, by overexpressing cadherins inhibits its signaling activity (Fagotto et al, 1996;Sanson et al, 1996;Simcha et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

et al. 2000

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b-Catenin and plakoglobin are closely related armadillo family proteins with shared and distinct properties; Both are associated with cadherins in actin-containing adherens junctions. Plakoglobin is also found in desmosomes where it anchors intermediate ®laments to the desmosomal plaques. b-Catenin, on the other hand, is a component of the Wnt signaling pathway, which is involved in embryonic morphogenesis and tumorigenesis. A key step in the regulation of this pathway involves modulation of b-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of bcatenin and its degradation by the ubiquitin-proteasome system. Plakoglobin can also associate with members of this complex, but inhibition of proteasomal degradation has little e ect on its levels while dramatically increasing the levels of b-catenin. b-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of b-catenin. To elucidate the basis for the apparent di erences in the turnover of bcatenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of b-TrCP, lacking the F-box, can stabilize the endogenous b-catenin leading to its nuclear translocation and induction of b-catenin/ LEF-1-directed transcription, without a ecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with b-TrCP, e ciently competed with b-catenin for binding to b-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of b-catenin. These results suggest that while both plakoglobin and b-catenin can comparably interact with b-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.

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Overexpression of cadherins and underexpression of ?-catenin inhibit dorsal mesoderm induction in early Xenopus embryos

Cited by 627 publications

References 52 publications

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

A novel RIPK4–IRF6 connection is required to prevent epithelial fusions characteristic for popliteal pterygium syndromes

The C/EBP homologous protein CHOP (GADD153) is an inhibitor of Wnt/TCF signals

Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system

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