Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin

Postnatal Expansion of the Pancreatic β-Cell Mass Is Dependent on Survivin Yuying Jiang 1 , Wataru Nishimura 2 , Deborah Devor-Henneman 3 , Donna Kusewitt 3 , Haijuan Wang 4 , Michael P. Holloway 1 4 , Takehiko Dohi 5 , Edmond Sabo 6 , Michael L. Robinson 7 , Dario C. Altieri 5 , Arun Sharma 2 and Rachel A. Altura 1 4 1 The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 2 Joslin Diabetes Center, Harvard Medical School, Boston Massachusetts 3 Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 4 Department of Pediatrics, Brown University, Providence, Rhode Island 5 Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 6 Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 7 Department of Zoology, Miami University, Oxford, Ohio Corresponding author: Rachel A. Altura, rachel_altura{at}brown.edu Abstract OBJECTIVE— Diabetes results from a deficiency of functional β-cells due to both an increase in β-cell death and an inhibition of β-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin , might also be important for β-cells. RESEARCH DESIGN AND METHODS— We generated mice harboring a conditional deletion of survivin in pancreatic endocrine cells using mice with a Pax-6- Cre transgene promoter construct driving tissue-specific expression of Cre-recombinase in these cells. We performed metabolic studies and immunohistochemical analyses to determine the effects of a mono- and biallelic deletion of survivin . RESULTS— Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in β-cell number after birth, leading to hyperglycemia and early-onset diabetes by 4 weeks of age. Serum insulin levels were significantly decreased in animals lacking endocrine cell survivin, with relative stability of other hormones. Exogenous expression of survivin in mature β-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in β-cell mass, confirming the specificity of the survivin effect in these cells. CONCLUSIONS— Our findings implicate survivin in the maintenance of β-cell mass through both replication and antiapo