A role for cadherins in tissue formation.

We have produced null mutant mouse embryonic stem cells for the cell adhesion molecule E-cadherin. Such E-cadherin-/- ES cells are defective in cell aggregation; this defect can be corrected by transfection with cDNA for either E-cadherin or N-cadherin driven by a constitutive promoter. The presence (or absence) of E-cadherin regulates the expression of the transcription factor T-brachyury, indicating that cadherins play a role in linking cell surface receptors and gene expression. Comparative analysis of the parental and the genetically altered ES cell lines was performed to examine cell differentiation and the capability to form organized tissues. While differentiating E-cadherin-/- ES cells are still able to express various early and late differentiation markers, they show a clear-cut deficiency in forming organized structures. This phenotype can be rescued by constitutive expression of E-cadherin, which results exclusively in formation of epithelia. In contrast, rescue transfectants expressing N-cadherin show no epithelial structures, instead forming neuroepithelium and cartilage. These results provide the first evidence that specific cadherins directly stimulate differentiation into certain types of tissues.

[1]  M. Takeichi,et al.  Cadherin cell adhesion receptors as a morphogenetic regulator. , 1991, Science.

[2]  M. Ringwald,et al.  The structure of cell adhesion molecule uvomorulin. Insights into the molecular mechanism of Ca2+‐dependent cell adhesion. , 1987, The EMBO journal.

[3]  E. Wieschaus,et al.  Spatial expression of the Drosophila segment polarity gene armadillo is posttranscriptionally regulated by wingless , 1990, Cell.

[4]  Philip L. Townes,et al.  Directed movements and selective adhesion of embryonic amphibian cells , 1955 .

[5]  R. Kemler,et al.  Embryonic stem cell culture and gene targeting in transgenic mice. , 1989, Molecular biology & medicine.

[6]  S. Butz,et al.  Distinct cadherin—catenin complexes in Ca2+ dependent cell—cell adhesion , 1994, FEBS letters.

[7]  Peter Gruss,et al.  Pax in development , 1992, Cell.

[8]  M. Takeichi,et al.  Fetal brain subdivisions defined by R- and E-cadherin expressions: evidence for the role of cadherin activity in region-specific, cell-cell adhesion. , 1995, Developmental biology.

[9]  M. Takeichi,et al.  Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development , 1986, Nature.

[10]  G. Lyons,et al.  Expression of NCAM isoforms during skeletal myogenesis in the mouse embryo , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  A. Nose,et al.  Neural cadherin: role in selective cell-cell adhesion. , 1989, Science.

[12]  J. Nadeau,et al.  Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos. , 1992, Development.

[13]  B. Gumbiner.  Signal transduction of beta-catenin. , 1995, Current opinion in cell biology.

[14]  C. Kintner.  Regulation of embryonic cell adhesion by the cadherin cytoplasmic domain , 1992, Cell.

[15]  Peter D. Kwong,et al.  Structural basis of cell-cell adhesion by cadherins , 1995, Nature.

[16]  R. Hynes.  Specificity of cell adhesion in development: the cadherin superfamily. , 1992 .

[17]  H. Schöler,et al.  Octamania: the POU factors in murine development. , 1991, Trends in genetics : TIG.

[18]  C. Dani,et al.  Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. , 1985, Nucleic acids research.

[19]  R. Balling,et al.  Cloning and expression analysis of a novel mesodermally expressed cadherin. , 1995, Developmental biology.

[20]  M. Takeichi.  Morphogenetic roles of classic cadherins. , 1995, Current opinion in cell biology.

[21]  D. Vestweber,et al.  Identification of a putative cell adhesion domain of uvomorulin. , 1985, The EMBO journal.

[22]  P. Brûlet,et al.  Monoclonal antibodies against trophectoderm-specific markers during mouse blastocyst formation. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[23]  D. Vestweber,et al.  Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues. , 1984, Experimental cell research.

[24]  M. Ikura,et al.  Solution structure of the epithelial cadherin domain responsible for selective cell adhesion , 1995, Science.

[25]  T. Uemura,et al.  A Drosophila homolog of cadherin associated with armadillo and essential for embryonic cell-cell adhesion. , 1994, Developmental biology.

[26]  L. Larue,et al.  E-cadherin null mutant embryos fail to form a trophectoderm epithelium. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[27]  R Kemler,et al.  The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. , 1985, Journal of embryology and experimental morphology.

[28]  R. Kemler.  From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. , 1993, Trends in genetics : TIG.

[29]  A. Nose,et al.  Expression and role of E- and P-cadherin adhesion molecules in embryonic histogenesis. I. Lung epithelial morphogenesis. , 1989, Development.

[30]  B. Gumbiner,et al.  Disruption of gastrulation movements in Xenopus by a dominant-negative mutant for C-cadherin. , 1995, Developmental biology.

[31]  W. Staines,et al.  Murine PGK‐1 promoter drives widespread but not uniform expression in transgenic mice , 1994, Developmental dynamics : an official publication of the American Association of Anatomists.

[32]  M. Wiles,et al.  Hematopoietic commitment during embryonic stem cell differentiation in culture. , 1993, Molecular and cellular biology.

[33]  C. Damsky,et al.  Developmentally regulated expression of the cell-cell adhesion glycoprotein cell-CAM 120/80 in peri-implantation mouse embryos and extraembryonic membranes. , 1986, Developmental biology.

[34]  E. Plow,et al.  The Cytoplasmic Domain of , 1996, The Journal of Biological Chemistry.

[35]  G. Edelman,et al.  Cell adhesion molecules: implications for a molecular histology. , 1991, Annual review of biochemistry.

[36]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[37]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[38]  E. Olson,et al.  A gene with homology to the myc similarity region of MyoD1 is expressed during myogenesis and is sufficient to activate the muscle differentiation program. , 1989, Genes & development.

[39]  P. Nielsen,et al.  In vitro generation of lymphoid precursors from embryonic stem cells. , 1994, The EMBO journal.

[40]  C. Babinet,et al.  Surface antigen in early differentiation. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[41]  I. Nabi,et al.  Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules , 1995, The Journal of cell biology.

[42]  B. Gumbiner,et al.  Selective disruption of E-cadherin function in early Xenopus embryos by a dominant negative mutant. , 1994, Development.

[43]  S. Butz,et al.  Expression of catenins during mouse embryonic development and in adult tissues. , 1995, Cell adhesion and communication.

[44]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .

[45]  R. Kemler,et al.  The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. , 1989, The EMBO journal.

[46]  J. Thiery,et al.  Differential perturbations in the morphogenesis of anterior structures induced by overexpression of truncated XB- and N-cadherins in Xenopus embryos , 1994, The Journal of cell biology.

[47]  C. Holt,et al.  Cadherin-mediated cell interactions are necessary for the activation of MyoD in Xenopus mesoderm. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  B. Herrmann,et al.  Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos. , 1991, Development.

[49]  G. Edelman,et al.  Antibodies to liver cell adhesion molecule perturb inductive interactions and alter feather pattern and structure. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[50]  G. Edelman.  Cell adhesion and morphogenesis: the regulator hypothesis. , 1984, Proceedings of the National Academy of Sciences of the United States of America.