Differential Requirement for the Dual Functions of β-catenin in Embryonic Stem Cell Self-renewal and Germ Layer Formation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2011 Jun 21

PMID 21685890

Citations 142

Authors

Natalia Lyashenko

Markus Winter

Domenico Migliorini

Travis Biechele

Randall T Moon

Christine Hartmann

Affiliations

Soon will be listed here.

Abstract

Canonical Wnt signalling has been implicated in mouse and human embryonic stem cell (ESC) maintenance; however, its requirement is controversial. β-catenin is the key component in this highly conserved Wnt pathway, acting as a transcriptional transactivator. However, β-catenin has additional roles at the plasma membrane regulating cell-cell adhesion, complicating the analyses of cells/tissues lacking β-catenin. We report here the generation of a Ctnnb1 (β-catenin)-deficient mouse ESC (mESC) line and show that self-renewal is maintained in the absence of β-catenin. Cell adhesion is partially rescued by plakoglobin upregulation, but fails to be maintained during differentiation. When differentiated as aggregates, wild-type mESCs form descendants of all three germ layers, whereas mesendodermal germ layer formation and neuronal differentiation are defective in Ctnnb1-deficient mESCs. A Tcf/Lef-signalling-defective β-catenin variant, which re-establishes cadherin-mediated cell adhesion, rescues definitive endoderm and neuroepithelial formation, indicating that the β-catenin cell-adhesion function is more important than its signalling function for these processes.

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References

Brons I, Smithers L, Trotter M, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes S . Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. 2007; 448(7150):191-5. DOI: 10.1038/nature05950. View

Lindsley R, Gill J, Kyba M, Murphy T, Murphy K . Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm. Development. 2006; 133(19):3787-96. DOI: 10.1242/dev.02551. View

Arnold S, Stappert J, Bauer A, Kispert A, Herrmann B, Kemler R . Brachyury is a target gene of the Wnt/beta-catenin signaling pathway. Mech Dev. 2000; 91(1-2):249-58. DOI: 10.1016/s0925-4773(99)00309-3. View

Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991; 108(2):193-9. DOI: 10.1016/0378-1119(91)90434-d. View

Ohsugi M, Hwang S, Butz S, Knowles B, Solter D, Kemler R . Expression and cell membrane localization of catenins during mouse preimplantation development. Dev Dyn. 1996; 206(4):391-402. DOI: 10.1002/(SICI)1097-0177(199608)206:4<391::AID-AJA5>3.0.CO;2-D. View

Miller J, Moon R . Analysis of the signaling activities of localization mutants of beta-catenin during axis specification in Xenopus. J Cell Biol. 1997; 139(1):229-43. PMC: 2139814. DOI: 10.1083/jcb.139.1.229. View

Fukunaga Y, Liu H, Shimizu M, Komiya S, Kawasuji M, Nagafuchi A . Defining the roles of beta-catenin and plakoglobin in cell-cell adhesion: isolation of beta-catenin/plakoglobin-deficient F9 cells. Cell Struct Funct. 2005; 30(2):25-34. DOI: 10.1247/csf.30.25. View

Teuliere J, Faraldo M, Shtutman M, Birchmeier W, Huelsken J, Thiery J . beta-catenin-dependent and -independent effects of DeltaN-plakoglobin on epidermal growth and differentiation. Mol Cell Biol. 2004; 24(19):8649-61. PMC: 516731. DOI: 10.1128/MCB.24.19.8649-8661.2004. View

Williams B, Barish G, Klymkowsky M, Varmus H . A comparative evaluation of beta-catenin and plakoglobin signaling activity. Oncogene. 2000; 19(50):5720-8. DOI: 10.1038/sj.onc.1203921. View

10.

Umehara H, Kimura T, Ohtsuka S, Nakamura T, Kitajima K, Ikawa M . Efficient derivation of embryonic stem cells by inhibition of glycogen synthase kinase-3. Stem Cells. 2007; 25(11):2705-11. DOI: 10.1634/stemcells.2007-0086. View

11.

Ben-Zeev A, Geiger B . Differential molecular interactions of beta-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol. 1998; 10(5):629-39. DOI: 10.1016/s0955-0674(98)80039-2. View

12.

Yamaguchi T, Takada S, Yoshikawa Y, Wu N, McMahon A . T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Genes Dev. 2000; 13(24):3185-90. PMC: 317203. DOI: 10.1101/gad.13.24.3185. View

13.

Giannini A, Vivanco M, Kypta R . alpha-catenin inhibits beta-catenin signaling by preventing formation of a beta-catenin*T-cell factor*DNA complex. J Biol Chem. 2000; 275(29):21883-8. DOI: 10.1074/jbc.M001929200. View

14.

Kofron M, Spagnuolo A, Klymkowsky M, Wylie C, Heasman J . The roles of maternal alpha-catenin and plakoglobin in the early Xenopus embryo. Development. 1997; 124(8):1553-60. DOI: 10.1242/dev.124.8.1553. View

15.

Maeda O, Usami N, Kondo M, Takahashi M, Goto H, Shimokata K . Plakoglobin (gamma-catenin) has TCF/LEF family-dependent transcriptional activity in beta-catenin-deficient cell line. Oncogene. 2003; 23(4):964-72. DOI: 10.1038/sj.onc.1207254. View

16.

Soncin F, Mohamet L, Eckardt D, Ritson S, Eastham A, Bobola N . Abrogation of E-cadherin-mediated cell-cell contact in mouse embryonic stem cells results in reversible LIF-independent self-renewal. Stem Cells. 2009; 27(9):2069-80. DOI: 10.1002/stem.134. View

17.

Sustmann C, Flach H, Ebert H, Eastman Q, Grosschedl R . Cell-type-specific function of BCL9 involves a transcriptional activation domain that synergizes with beta-catenin. Mol Cell Biol. 2008; 28(10):3526-37. PMC: 2423143. DOI: 10.1128/MCB.01986-07. View

18.

Kemler R . From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993; 9(9):317-21. DOI: 10.1016/0168-9525(93)90250-l. View

19.

Zhou J, Qu J, Yi X, Graber K, Huber L, Wang X . Upregulation of gamma-catenin compensates for the loss of beta-catenin in adult cardiomyocytes. Am J Physiol Heart Circ Physiol. 2006; 292(1):H270-6. DOI: 10.1152/ajpheart.00576.2006. View

20.

Lien W, Klezovitch O, Fernandez T, Delrow J, Vasioukhin V . alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway. Science. 2006; 311(5767):1609-12. PMC: 2556178. DOI: 10.1126/science.1121449. View