Research article summary (published 5 Nov 2007):

Wnt6 induces the specification and epithelialization of F9 embryonal carcinoma cells to primitive endoderm.

Full Abstract

Epithelial-to-mesenchymal transitions (EMTs) play key roles in the normal development of an organism as well as its demise following the metastasis of a malignant tumour. An EMT during early mouse development results in the differentiation of primitive endoderm into the parietal endoderm that forms part of the parietal yolk sac. In the embryo, primitive endoderm develops from cells in the inner cell mass, but the signals that instruct these cells to become specified and adopt an epithelial fate are poorly understood. The mouse F9 teratocarcinoma cell line, a model that can recapitulate the in vivo primitive to parietal endoderm EMT, has been used extensively to elucidate the signalling cascades involved in extraembryonic endoderm differentiation. Here, we identified Wnt6 as a gene up-regulated in F9 cells in response to RA and show that Wnt6 expressing cells or cells exposed to Wnt6 conditioned media form primitive endoderm. Wnt6 induction of primitive endoderm is accompanied by beta-catenin and Snail1 translocation to the nucleus and the appearance of cytokeratin intermediate filaments. Attenuating glycogen synthase kinase 3 activity using LiCl gave similar results, but the fact that cells de-differentiate when LiCl is removed reveals that other signalling pathways are required to maintain cells as primitive endoderm. Finally, Wnt6-induced primitive endodermal cells were tested to determine their competency to complete the EMT and differentiate into parietal endoderm. Towards that end, results show that up-regulating protein kinase A activity is sufficient to induce markers of parietal endoderm. Together, these findings indicate that undifferentiated F9 cells are responsive to canonical Wnt signalling, which negatively regulates glycogen synthase kinase 3 activity leading to the epithelialization and specification of primitive endoderm competent to receive additional signals required for EMT. Considering the ability of F9 cells to mimic an in vivo EMT, the identification of this Wnt6-beta-catenin-Snail signalling cascade has broad implications for understanding EMT mechanisms in embryogenesis and metastasis.

Author information

Author/s: Krawetz, Roman (R); Kelly, Gregory M (GM);

Affiliation: Department of Biology, Molecular Genetics Unit, University of Western Ontario, London, Ontario, Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Cellular signalling (Cell Signal), published in England. (Language: eng)

Reference: 2008-Mar; vol 20 (issue 3) : pp 506-17

Dates: Created 2008/01/21; Completed 2008/03/27;

PMID: 18160257, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Active Transport, Cell Nucleus Animals Body Patterning - drug effects Bucladesine - pharmacology COS Cells Cell Differentiation - drug effects Cell Line, Tumor Cercopithecus aethiops Culture Media, Conditioned - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Embryonal Carcinoma Stem Cells - drug effects; enzymology; metabolism; pathology Endoderm - drug effects; enzymology; metabolism; pathology Epithelial Cells - drug effects; enzymology; metabolism; pathology Gene Expression Regulation, Developmental

Glycogen Synthase Kinase 3 - antagonists & inhibitors; metabolism Intermediate Filaments - metabolism Lithium Chloride - pharmacology Mice Proto-Oncogene Proteins - genetics; metabolism RNA, Messenger - metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction - drug effects Transcription Factors - metabolism Transfection Tretinoin - pharmacology Up-Regulation Wnt Proteins - genetics; metabolism beta Catenin - metabolism

Associated Chemicals: Catnb protein, mouse (0) ; Culture Media, Conditioned (0) ; Proto-Oncogene Proteins (0) ; RNA, Messenger (0) ; Transcription Factors (0) ; Wnt Proteins (0) ; Wnt6 protein, mouse (0) ; beta Catenin (0) ; snail family transcription factors (0) ; Tretinoin (302-79-4) ; Bucladesine (362-74-3) ; Lithium Chloride (7447-41-8) ; Glycogen Synthase Kinase 3 (EC 2.7.1.37) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)

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