Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model Xiaohong Wu1*, Qinfeng Zhang 1 , Xiaojing Wang1, Jiayu Zhu 1 , Kuangfeng Xu 1 , Hitoshi Okada2, Rennian Wang 3 , Minna Woo4,5,6 1 Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China, 2 Division of Signaling Biology, Ontario Cancer Institute, Toronto, Ontario, Canada, 3 Department of Physiology and Pharmacology, Children’s Health Research Institute, University of Western Ontario, London, Canada, 4 Toronto General Research Institute, Toronto, Ontario, Canada, 5 Department of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, 6 Division of Endocrinology and Keenan Research Centre in the Li KaShing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada Abstract Aims/Hypothesis: Pancreatic beta-cell mass expands through adulthood under certain conditions. The related molecular mechanisms are elusive. This study was designed to determine whether surviving (also known as Birc5), which is transiently expressed perinatally in islets, was required for beta-cell mass expansion in the pancreatic duct-ligated mouse model. Methods: Mice with beta cell–specific deletion of survivin (RIPCre+survivinfl/fl) and their control littermates (RIPCre+survivin+/ +) were examined to determine the essential role of survivin in partial pancreatic duct ligation (PDL)-induced beta-cell proliferation, function and survival. Results: Resurgence of survivin expression occurred as early as day 3 post-PDL. By day 7 post-PDL, control mice showed significant expansion of beta-cell mass and increase in beta-cell proliferation and islet number in the ligated tail of the pancreas. However, mice deficient in beta-cell survivin showed a defect in beta-cell mass expansion and proliferation with a marked attenuation in the increase of total islet number, largely due to an impairment in the increase in number of larger islets while sparing the increase in number of small islets in the ligated tail of pancreas, resulting in insufficient insulin secretion and glucose intolerance. Importantly however, beta cell neogenesis and apoptosis were not affected by the absence of survivin in beta cells after PDL. Conclusions/Interpretation: Our results indicate that survivin is essential for beta-cell mass expansion after PDL. Survivin appears to exhibit a preferential requirement for proliferation of preexisting beta cells. Citation: Wu X, Zhang Q, Wang X, Zhu J, Xu K, et al. (2012) Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model. PLoS ONE 7(8): e41976. doi:10.1371/journal.pone.0041976 Editor: Francis C. Lynn, University of British Columbia, Canada Received March 14, 2012; Accepted June 27, 2012; Published August 1, 2012 Copyright: 2012 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants to X. Wu from the National Natural Science Foundation of China (30971404/C140406 and 81070621/H0704), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Human Resource Ministry and State Education Ministry, International Science and Technology Cooperation Plan - the Key National and Regional Research and Development Cooperation Projects (BZ2011042) and the Jiangsu Government Scholarship for Overseas Studies. MW was supported by grants from the Canadian Institutes of Health Research (MOP-201188 and MOP-191501). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: drxhwu@njmu.edu.cn Introduction As type 1 and type 2 diabetes result from absolute or relative deficiencies in beta-cell mass, respectively, understanding how beta-cell mass is regulated can lead to new therapeutic options. Beta cells replicate slowly after birth [1], but proliferation can be stimulated under various conditions, including obesity, pregnancy and in response to growth factors [2]. However, the mechanism by which new beta cells are formed in adults is still controversial. Genetic lineage tracing studies provide evidence that pre-existing beta cells, rather than stem/progenitor cells, are the major source of new beta cells in adult mice both under normal physiological conditions and after 50% to 70% pancreatectomy [3,4]. However, a recent study [5] in mice has shown that new beta cells are generated from facultative adult progenitor cells (neogenesis) in response to pancreatic injury, in a manner reminiscent of embryonic endocrine cell differentiation. Survivin (also known as Birc5) is the smallest member of the inhibitor of apoptosis protein (IAP) gene family [6]. Initially, survivin was described as an anti-apoptosis gene [7]. However, further studies have revealed that survivin is a multifunctional protein that intersects fundamental networks of cellular processes, including cell death, cell division and cellular adaptation [8–10]. Germline deletion of survivin leads to early embryonic lethality at E3.5 [11]. Tissue-specific knockout of survivin in thymocytes, neuronal precursors, endothelial cells or haematopoietic progeni- tors resulted in impaired cell proliferation, cell cycle arrest, apoptosis, or mitotic spindle formation, illustrating a complex physiological role for survivin in normal cell development [12–15]. Previous studies have shown that survivin is expressed in beta cells of fetal human pancreas,but not in adult islets [16,17]. PLoS ONE | www.plosone.org 1 August 2012 | Volume 7 | Issue 8 | e41976