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J. Biol. Chem., Vol. 282, Issue 40, 29701-29711, October 5, 2007

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Regulation of Mesodermal Differentiation of Mouse Embryonic Stem Cells by Basement Membranes^*

Hironobu Fujiwara, Yoshitaka Hayashi¹, Noriko Sanzen, Reiko Kobayashi, Charles N. Weber, Tomomi Emoto, Sugiko Futaki, Hitoshi Niwa^¶, Patricia Murray^||, David Edgar^**, and Kiyotoshi Sekiguchi²

From the Institute for Protein Research, Osaka University, Osaka 565-0871, Japan, the Sekiguchi Biomatrix Signaling Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Agency, Aichi Medical University, Aichi 480-1195, Japan, the ^¶Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Hyogo 650-0047, Japan, the ^||School of Biological Science, University of Liverpool, Liverpool L69 7ZB, United Kingdom, and the ^**School of Biomedical Science, University of Liverpool, Liverpool L69 3GE, United Kingdom

Basement membranes (BMs) have been implicated in cell fate determination during development. Embryoid bodies (EBs) derived from mouse embryonic stem cells deficient in the laminin 1 chain are incapable of depositing a BM, resulting in failure of primitive ectoderm epithelialization. To elucidate the mechanisms involved in this phenomenon, we compared the gene expression profiles of EBs with or without a BM to identify the genes showing BM-dependent expression. We found that the expressions of marker genes for the epithelial-mesenchymal transition (EMT), including the transcription factor Snai2, were up-regulated in LAMC1^-/- EBs, whereas restoration of a BM to LAMC1^-/- EBs suppressed the up-regulation of these genes. Overexpression of Snai2 induced the EMT in control EBs by molecular and morphological criteria, suggesting that suppression of the EMT regulatory genes is involved in BM-dependent epithelialization of primitive ectoderm. Despite the failure of primitive ectoderm epithelialization in BM-deficient EBs, mesodermal differentiation was not compromised, but rather accelerated. Furthermore, at later stages of control EB differentiation, the BM was disrupted at the gastrulation site where mesodermal markers were strongly expressed only in cells that had lost contact with the BM. Taken together, these results indicate that the BM prevents the EMT and precocious differentiation of primitive ectoderm toward mesoderm in EBs, implying that BMs are important for the control of mammalian gastrulation.

Received for publication, December 14, 2006 , and in revised form, August 3, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4 and Tables S1 and S2.

¹ Present address: Dept. of Genetics, Research Institute of Environmental Medicine, Nagoya University, Aichi 464-8601, Japan. To whom correspondence may be addressed. Tel.: 81-52-789-3874; Fax: 81-52-789-3876; E-mail: hayashiy{at}riem.nagoya-u.ac.jp.

² To whom correspondence may be addressed. Tel.: 81-6-6879-8617; Fax: 81-6-6879-8619; E-mail: sekiguch{at}protein.osaka-u.ac.jp.

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