GRP94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion.
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.
Wanderling
Sherry
S
Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Simen
Birgitte B
BB
Ostrovsky
Olga
O
Ahmed
Noreen T
NT
Vogen
Shawn M
SM
Gidalevitz
Tali
T
Argon
Yair
Y
D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D020964:Embryo Loss; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000166:cytology; D004628:Embryonic Structures / Q000166:cytology; D005775:Gastrula / Q000166:cytology; D017353:Gene Deletion; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D007335:Insulin-Like Growth Factor II / Q000172:deficiency / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D010641:Phenotype
D015415:Biomarkers; D008562:Membrane Glycoproteins; C053387:endoplasmin; D007335:Insulin-Like Growth Factor II