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J. Biol. Chem., Vol. 282, Issue 5, 3379-3390, February 2, 2007

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Ceramide Regulates Atypical PKC/-mediated Cell Polarity in Primitive Ectoderm Cells

A NOVEL FUNCTION OF SPHINGOLIPIDS IN MORPHOGENESIS^*

Kannan Krishnamurthy¹, Guanghu Wang¹, Jeane Silva, Brian G. Condie, and Erhard Bieberich²

From the Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912 and the ADepartment of Genetics, University of Georgia, Athens, Georgia 30602

In mammals, the primitive ectoderm is an epithelium of polarized cells that differentiates into all embryonic tissues. Our study shows that in primitive ectoderm cells, the sphingolipid ceramide was elevated and co-distributed with the small GTPase Cdc42 and cortical F-actin at the apicolateral cell membrane. Pharmacological or RNA interference-mediated inhibition of ceramide biosynthesis enhanced apoptosis and impaired primitive ectoderm formation in embryoid bodies differentiated from mouse embryonic stem cells. Primitive ectoderm formation was restored by incubation with ceramide or a ceramide analog. Ceramide depletion prevented plasma membrane translocation of PKC/, its interaction with Cdc42, and phosphorylation of GSK-3, a substrate of PKC/. Recombinant PKC formed a complex with the polarity protein Par6 and Cdc42 when bound to ceramide containing lipid vesicles. Our data suggest a novel mechanism by which a ceramide-induced, apicolateral polarity complex with PKC/ regulates primitive ectoderm cell polarity and morphogenesis.

Received for publication, August 15, 2006 , and in revised form, October 13, 2006.

^* This work was supported by National Institutes of Health Grant R01NS046835. 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-S3.

¹ The first two authors contributed equally to this study.

² To whom correspondence should be addressed: Inst. of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th St., Rm. CB-2803, Augusta, GA 30912. Tel.: 706-721-9113; Fax: 706-721-8685; E-mail: ebieberich{at}mail.mcg.edu.

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