This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vincent, M. Articles by Teitelman, G. Search for Related Content PubMed PubMed Citation Articles by Vincent, M. Articles by Teitelman, G.

Abrogation of Protein Convertase 2 Activity Results in Delayed Islet Cell Differentiation and Maturation, Increased -Cell Proliferation, and Islet Neogenesis

Department of Anatomy and Cell Biology, State University of New York (M.V., Y.G., M.R., G.T.), Brooklyn, New York 11203; Department of Medical Nutrition, Suzuka University of Medical Science and Technology (M.F.), Suzuka, Mie 510-02, Japan; and Howard Hughes Medical Institute, University of Chicago (G.W., D.S.), Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Gladys Teitelman, Ph.D., Department of Anatomy and Cell Biology, State University of New York, Health Science Center, 450 Clarkson Avenue, Brooklyn, New York 11203. E-mail: gteitelman{at}downstate.com.

To date, the role of pancreatic hormones in pancreatic islet growth and differentiation is poorly understood. To address this issue, we examined mice with a disruption in the gene encoding prohormone convertase 2 (PC2). These mice are unable to process proglucagon, prosomatostatin, and other neuroendocrine precursors into mature hormones. Initiation of insulin (IN) expression during development was delayed in PC2 mutant mice. Cells containing IN were first detected in knockout embryos on d 15 of development, 5 d later than in wild-type littermates. However, the IN⁺ cells of d 15 PC2 mutant mice coexpressed glucagon, as did the first appearing ß-cells of controls. In addition, lack of PC2 perturbed the pattern of expression of transcription factors presumed to be involved in the determination of the mature -cell phenotype. Thus, in contrast to controls, -cells of mutant mice had protracted expression of Nkx 6.1 and Pdx-1, but did not express Brn-4. Islets of adult mutant mice also contained cells coexpressing insulin and somatostatin, an immature cell type found only in islets of the wild-type strain during development. In addition to the effects on islet cell differentiation, the absence of PC2 activity resulted in a 3-fold increase in the rate of proliferation of proglucagon cells during the perinatal period. This increase contributed to the development of -cell hyperplasia during postnatal life. Furthermore, the total ß-cell volume was increased 2-fold in adult mutants compared with controls. This increase was due to islet neogenesis, as the number of islets per section was significantly higher in knockout mice compared with wild-type mice, whereas both strains had similar rates of IN cell proliferation. These results indicate that hormones processed by PC2 affected processes that regulate islet cell differentiation and maturation in embryos and adults.

This article has been cited by other articles:

				J.-i. Suzuki, Y. Murakami, K. Samejima, K. K. M. Ohtani, and T. Oka Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells Endocr. Relat. Cancer, June 1, 2009; 16(2): 649 - 659. [Abstract] [Full Text] [PDF]

				R. D. Wideman, S. D. Covey, G. C. Webb, D. J. Drucker, and T. J. Kieffer A Switch From Prohormone Convertase (PC)-2 to PC1/3 Expression in Transplanted {alpha}-Cells Is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice Diabetes, November 1, 2007; 56(11): 2744 - 2752. [Abstract] [Full Text] [PDF]

				J. Gromada, I. Franklin, and C. B. Wollheim {alpha}-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains Endocr. Rev., February 1, 2007; 28(1): 84 - 116. [Abstract] [Full Text] [PDF]

				P. M. Vuguin, M. H. Kedees, L. Cui, Y. Guz, R. W. Gelling, M. Nejathaim, M. J. Charron, and G. Teitelman Ablation of the Glucagon Receptor Gene Increases Fetal Lethality and Produces Alterations in Islet Development and Maturation Endocrinology, September 1, 2006; 147(9): 3995 - 4006. [Abstract] [Full Text] [PDF]

				S. Thyssen, E. Arany, and D. J. Hill Ontogeny of Regeneration of {beta}-Cells in the Neonatal Rat after Treatment with Streptozotocin Endocrinology, May 1, 2006; 147(5): 2346 - 2356. [Abstract] [Full Text] [PDF]

				A. H. Vesper, L. T. Raetzman, and S. A. Camper Role of Prophet of Pit1 (PROP1) in Gonadotrope Differentiation and Puberty Endocrinology, April 1, 2006; 147(4): 1654 - 1663. [Abstract] [Full Text] [PDF]

				R. McGirr, C. E. Ejbick, D. E. Carter, J. D. Andrews, Y. Nie, T. C. Friedman, and S. Dhanvantari Glucose Dependence of the Regulated Secretory Pathway in {alpha}TC1-6 Cells Endocrinology, October 1, 2005; 146(10): 4514 - 4523. [Abstract] [Full Text] [PDF]

				G. Flock, X. Cao, and D. J. Drucker Pdx-1 Is Not Sufficient for Repression of Proglucagon Gene Transcription in Islet or Enteroendocrine Cells Endocrinology, January 1, 2005; 146(1): 441 - 449. [Abstract] [Full Text] [PDF]

				G. C. Webb, A. Dey, J. Wang, J. Stein, M. Milewski, and D. F. Steiner Altered Proglucagon Processing in an {alpha}-Cell Line Derived from Prohormone Convertase 2 Null Mouse Islets J. Biol. Chem., July 23, 2004; 279(30): 31068 - 31075. [Abstract] [Full Text] [PDF]