Differential requirements for β-catenin during mouse development

Rudloff, Stefan; Kemler, Rolf

doi:10.1242/dev.085597

Cited by 53 publications

(47 citation statements)

References 51 publications

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“…Consistent with other recent studies (del Valle et al, 2013;Faunes et al, 2013;Rudloff and Kemler, 2012), however, our data do not preclude a non-transcriptional role for β-catenin in the maintenance of pluripotency in vitro.…”

Section: Research Articlesupporting

confidence: 93%

“…We show here that zygotic Porcn mutants fail to gastrulate and remain in an Oct3/4 + Otx2 + epiblast-like state, similar to Porcn epiblast-specific mutants. This not only phenocopies Wnt3 mutants (Liu et al, 1999), but also a group of 'canonical Wnt null' phenotypes, such as Wls (Fu et al, 2009), Mesd1 (Mesdc1 -Mouse Genome Informatics) (Hsieh et al, 2003), Lrp5/6 compound mutants (Kelly et al, 2004), and epiblast-specific Ctnnb1 mutants (Rudloff and Kemler, 2012). Strikingly, the phenotype of the downstream effector Ctnnb1 differs slightly (Haegel et al, 1995;Huelsken et al, 2000;Morkel et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

“…As ESCs are derived from the epiblast of blastocysts, it has been suggested that Wnt signaling is also required in the ICM in vivo. The fact that maternal zygotic Porcn mutants, as well as canonical Wnt receptor and Ctnnb1 mutants (Kelly et al, 2004;Rudloff and Kemler, 2012;Valenta et al, 2011), develop to gastrulation stages shows, however, that Porcndependent canonical Wnt signaling is not strictly required for the maintenance of the ICM in vivo. Further, in contrast to LIF signaling (Nichols et al, 2001), we show that Porcn-mediated Wnt signaling is not required for the prolonged maintenance of epiblast during diapause in vivo.…”

Section: Research Articlementioning

confidence: 99%

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Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

et al. 2013

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SUMMARYIn mice and humans the X-chromosomal porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands and thus represents a bottleneck for all Wnt signaling. We have generated a mouse line carrying a floxed allele for Porcn and used zygotic, oocyte-specific and visceral endoderm-specific deletions to investigate embryonic and extra-embryonic requirements for Wnt ligand secretion. We show that there is no requirement for Porcn-dependent secretion of Wnt ligands during preimplantation development of the mouse embryo. Porcn-dependent Wnts are first required for the initiation of gastrulation, where Porcn function is required in the epiblast but not the visceral endoderm. Heterozygous female embryos, which are mutant in both trophoblast and visceral endoderm due to imprinted X chromosome inactivation, complete gastrulation but display chorio-allantoic fusion defects similar to Wnt7b mutants. Our studies highlight the importance of Wnt3 and Wnt7b for embryonic and placental development but suggest that endogenous Porcn-dependent Wnt secretion does not play an essential role in either implantation or blastocyst lineage specification.

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Section: Research Articlesupporting

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Section: Research Articlementioning

confidence: 99%

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Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

et al. 2013

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“…␤-catenin flox/Ϫ cells respond to Wnt3a stimulation with the up-regulation of the canonical Wnt signaling targets Axin2, Cdx1, and brachyury (T) within 4 h after Wnt3a supplementation (25), and SR1-Cre-ERT2 are similarly Wnt3a responsive. 2 Interestingly, we could not observe a significant increase in the protein levels of chromatin-bound ␤-catenin in mES cells after Wnt3a, LiCl, or GSK3a inhibitor treatments (supplemental Fig.…”

Section: ␤-Catenin Chromatin Interactome In Mouse Embryonic Stem Cellsmentioning

confidence: 99%

Wnt3a-dependent and -independent Protein Interaction Networks of Chromatin-bound β-catenin in Mouse Embryonic Stem Cells

Yakulov

Raggioli

Franz

et al. 2013

Molecular & Cellular Proteomics

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Canonical Wnt signaling is repeatedly used during development to control cell fate, and it is often implicated in human cancer. ␤-catenin, the effector of Wnt signaling, has a dual function in the cell and is involved in both cell adhesion and transcription. Nuclear ␤-catenin controls transcription through association with transcription factors of the TCF family and the recruitment of epigenetic modifiers. In this study, we used a strategy combining the genetic manipulation of mouse embryonic stem cells with affinity purification and quantitative mass spectroscopy utilizing stable isotope labeling with amino acids in cell culture to study the interactome of chromatin-bound ␤-catenin with and without Wnt3a stimulation. We uncovered previously unknown interactions of ␤-catenin with transcription factors and chromatin-modifying complexes. The canonical Wnt signaling pathway plays multiple roles in development and is often dysregulated in human cancers (1). The key event in the canonical Wnt signaling is the regulation of ␤-catenin. Under normal conditions, the levels of ␤-catenin are low as a result of its phosphorylation by the destruction complex and subsequent ubiquitination and degradation by the proteasome (1). The destruction complex contains the scaffold proteins APC and Axin1, protein phosphatase 2a, and the kinases glycogen synthase kinase (GSK)-3␤ and casein kinase I alpha. Upon binding of Wnt ligands to the receptors Frizzled and LRP5/6, the destruction complex is turned off via translocation to the plasma membrane, where it binds Dishevelled. Thus, ␤-catenin is stabilized, translocates to the nucleus, and associates with TCF factors and with various proteins that are implicated in chromatin structure and RNA polymerase II regulation (1, 2).The interactions of ␤-catenin with chromatin effector proteins are concentrated at the C-terminal domain of ␤-catenin, as shown for the histone acetyltransferases CBP and p300, the histone methyltransferase MLL, the nucleosome repositioning SWI/SNF family member protein Brg1, the Mediator component MED12, and the BCL-9/Pygo complex, which has the ability to bind methylated H3K4 (2). It is not probable that all these bulky multiprotein assemblies simultaneously occupy the C-terminal domain of ␤-catenin. Other transcription factors use the same repertoire of co-activators via sequential or cycling recruitment (3). It is likely that ␤-catenin serves as a platform which orchestrates the sequential recruitment of chromatin remodeling factors in a stimulus-dependent manner.In mES 1 cells, the epigenetic regulation of gene expression has been shown to take place at the levels of DNA methylation, histone modification, nucleosome packaging and rearrangement, and higher order chromatin organization (4). Unique to key developmental genes in mES cells are bivalent chromatin domains with both activating and repressing marks, which contribute to the pluripotency potential of mES cells (5). Although Wnt/␤-catenin signaling has been shown to play a role in the self-renewal and plurip...

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“…Given the fundamental requirement for β-catenin in multicellular forms of life (Dickinson et al, 2011), as well as the presence of β-catenin (CTNNB1) in the mouse oocyte and the early activation of Ctnnb1 in the 2-cell embryo (Bauer and Willert, 2012;de Vries et al, 2004;Valenta et al, 2012), it was a surprise to find that there is no phenotypic effect in Ctnnb1 null offspring of Ctnnb1 +/− B6.129 mice until ∼5.5 days post coitum (dpc), when the well-known role of CTNNB1 in the Wnt signaling pathway becomes essential for gastrulation (Haegel et al, 1995;Huelsken et al, 2000;Rudloff and Kemler, 2012). These authors suggested that either plakoglobin, a closely related protein, or maternally contributed CTNNB1 is able to support preimplantation embryonic development.…”

Section: Introductionmentioning

confidence: 99%

β-catenin-mediated adhesion is required for successful preimplantation mouse embryo development

et al. 2016

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β-catenin (CTNNB1) is integral to cell adhesion and to the canonical Wnt signaling pathway. The effects of maternal and zygotic CTNNB1 on embryogenesis have each been separately assessed, whereas the effect of its total absence has not. As the 'traditional' conditional Ctnnb1 knockout alleles give rise to truncated CTNNB1 fragments, we designed a new knockout allele incapable of CTNNB1 production. Mouse embryos lacking intact maternal/zygotic CTNNB1 from two knockout strains were examined in detail. Preimplantation embryos are formed, yet abnormalities in their size and shape were found throughout pre-and early postimplantation development. In the absence of the zona pellucida, embryos lacking CTNNB1 undergo fission and these separated blastomeres can become small trophoblastic vesicles, which in turn induce decidual reactions. Comparing the severity of this defective adhesion phenotype in embryos bearing the null allele with those carrying the 'traditional' knockout allele suggests a hypomorphic effect of the truncated CTNNB1 protein fragment, an important observation with possible impact on previous and future studies.

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Differential requirements for β-catenin during mouse development

Cited by 53 publications

References 51 publications

Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

Porcn-dependent Wnt signaling is not required prior to mouse gastrulation

Wnt3a-dependent and -independent Protein Interaction Networks of Chromatin-bound β-catenin in Mouse Embryonic Stem Cells

β-catenin-mediated adhesion is required for successful preimplantation mouse embryo development

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