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Vol. 18, Issue 10, 3764-3775, October 2007

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GRP94 Is Essential for Mesoderm Induction and Muscle Development Because It Regulates Insulin-like Growth Factor Secretion

Sherry Wanderling^*,,, Birgitte B. Simen^*,,,||, Olga Ostrovsky^,¶, Noreen T. Ahmed^¶, Shawn M. Vogen^*, Tali Gidalevitz^*,#, and Yair Argon^*,,¶

*Department of Pathology and Committee on Cell Physiology, The University of Chicago, Chicago, IL 60637; and ^¶Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104

Submitted March 26, 2007; Revised June 18, 2007; Accepted July 6, 2007
Monitoring Editor: Jeffrey Brodsky

Because only few of its client proteins are known, the physiological roles of the endoplasmic reticulum chaperone glucose-regulated protein 94 (GRP94) are poorly understood. Using targeted disruption of the murine GRP94 gene, we show that it has essential functions in embryonic development. grp94–/– embryos die on day 7 of gestation, fail to develop mesoderm, primitive streak, or proamniotic cavity. grp94–/– ES cells grow in culture and are capable of differentiation into cells representing all three germ layers. However, these cells do not differentiate into cardiac, smooth, or skeletal muscle. Differentiation cultures of mutant ES cells are deficient in secretion of insulin-like growth factor II and their defect can be complemented with exogenous insulin-like growth factors I or II. The data identify insulin-like growth factor II as one developmentally important protein whose production depends on the activity of GRP94. Keywords: chaperone/HSP90/Insulin-like growth factors/mouse development.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

¹ The official gene name, as designated in the Mouse Genome Informatics (MGI) database at the Jackson lab, is Tra1 (tumor rejection antigen 1). GRP94 is also known by the names gp96, HSP108, ERp99, and endoplasmin.

These authors contributed equally to this work and should be considered co-first authors.

Present addresses: Department of Medicine, The University of Chicago, Chicago, IL 60637;

^|| 454 Life Sciences, 20 Commercial Street, Branford, CT 06405;

^# Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, IL 60208.

Address correspondence to: Yair Argon (yargon{at}mail.med.upenn.edu)

Abbreviations used: AVE, anterior visceral endoderm; EB, embryoid body; ES cells, embryonic stem cells; GRP, glucose regulated protein; HSP, heat shock protein; IGF, insulin-like growth factor; VE, visceral endoderm.

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