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Molecular and Cellular Biology, June 2002, p. 3864-3874, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3864-3874.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The PERK Eukaryotic Initiation Factor 2{alpha} Kinase Is Required for the Development of the Skeletal System, Postnatal Growth, and the Function and Viability of the Pancreas

Peichuan Zhang,1 Barbara McGrath,1 Sheng'ai Li,1 Ami Frank,1 Frank Zambito,1 Jamie Reinert,1 Maureen Gannon,2 Kun Ma,3 Kelly McNaughton,4 and Douglas R. Cavener1,4*

Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802,1 Departments of Medicine and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine,2 Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37235,4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 462023

Received 12 December 2001/ Returned for modification 6 February 2002/ Accepted 21 February 2002

Phosphorylation of eukaryotic initiation factor 2{alpha} (eIF-2{alpha}) is typically associated with stress responses and causes a reduction in protein synthesis. However, we found high phosphorylated eIF-2{alpha} (eIF-2{alpha}[P]) levels in nonstressed pancreata of mice. Administration of glucose stimulated a rapid dephosphorylation of eIF-2{alpha}. Among the four eIF-2{alpha} kinases present in mammals, PERK is most highly expressed in the pancreas, suggesting that it may be responsible for the high eIF-2{alpha}[P] levels found therein. We describe a Perk knockout mutation in mice. Pancreata of Perk-/- mice are morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerate, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas exhibits a reduction in the synthesis of several major digestive enzymes and succumbs to massive apoptosis after the fourth postnatal week. Perk-/- mice also exhibit skeletal dysplasias at birth and postnatal growth retardation. Skeletal defects include deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects are associated with defects in the rough endoplasmic reticulum of the major secretory cells that comprise the skeletal system and pancreas. The skeletal, pancreatic, and growth defects are similar to those seen in human Wolcott-Rallison syndrome.

* Corresponding author. Mailing address: Department of Biology, 208 Mueller Lab, The Pennsylvania State University, University Park, PA 16802. Phone: (814) 865-4562. Fax: (814) 865-6193. E-mail: drc9{at}psu.edu.

Molecular and Cellular Biology, June 2002, p. 3864-3874, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3864-3874.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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