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MBC in Press, published online ahead of print July 18, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0275

A more recent version of this article appeared on October 1, 2007
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Submitted on March 26, 2007
Revised on June 18, 2007
Accepted on July 6, 2007

GRP94 Is Essential for Mesoderm Induction and Muscle Development because It Regulates Igf Secretion

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

*Department of Pathology and {sect}Committee on Cell Physiology, The University of Chicago, Chicago, IL 60637; Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

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.

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

Present addresses: {ddagger}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.

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




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