Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity Vijay Pratap Singh, B. Jyothi Lakshmi, Shalu Singh, Vanya Shah, Sandeep Goel, D. Partha Sarathi, Satish Kumar* Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research (CSIR), Hyderabad, India Abstract WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes. Citation: Singh VP, Lakshmi BJ, Singh S, Shah V, Goel S, et al. (2012) Lack of Wdr13 Gene in Mice Leads to Enhanced Pancreatic Beta Cell Proliferation, Hyperinsulinemia and Mild Obesity. PLoS ONE 7(6): e38685. doi:10.1371/journal.pone.0038685 Editor: Thierry Alquier, Montreal Diabetes Research Center, Canada Received December 20, 2011; Accepted May 8, 2012; Published June 8, 2012 Copyright: 2012 Singh 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: The first author was supported by a fellowship from the Council of Scientific and Industrial Research, New Delhi. This manuscript is an outcome of the research funds provided by the Council of Scientific and Industrial Research, New Delhi, Department of Science and Technology, Government of India, New Delhi and Department of Biotechnology, Government of India, New Delhi. 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: satishk@ccmb.res.in Introduction WD (tryptophan and aspartate)-repeat proteins belong to a large family of structurally related proteins, members of which have diverse functions such as cell cycle regulation, transcription, chromatin organization and protein trafficking [1,2]. These proteins provide a platform for protein-protein interactions. WDR13 protein is a member of this family and localizes to the nucleus [3]. Wdr13 gene is highly conserved in vertebrates. This gene is located on the X-chromosome at locus Xp11.23 and XA1.1 in human and mouse, respectively. In human, X chromosomal deletions including this gene have been associated with mental retardation, obesity and xeroderma [4,5,6,7]. Wdr13 gene expresses in most of the tissues [8], the highest level of expression being in pancreas, brain, testis and ovaries. Several WD-repeat proteins have been identified that are expressed in pancreatic beta cells and have roles in beta cell proliferation [9,10]. The beta cell mass is regulated by the balance between neogenesis/proliferation and apoptosis/necrosis. In mice, differ- entiation of islet precursor and expansion are responsible for beta cell neogenesis until the first week of life [11,12]. Thereafter, expansion of existing beta cells is the main source of newly formed beta cells [13,14]. In pathological conditions there can be alpha to beta cell trans-differentiation [15]. Various cell cycle regulators have been identified that have role in pancreatic beta cell proliferation [16]. Cell cycle progression in pancreatic islet is controlled by cyclins, cyclin dependent kinases (CDKs), cyclin dependent kinase inhibitors and hormones [16,17]. Pancreatic islet mass, insulin production and body weight are inter-related [12,18]. Insulin levels have been positively correlated with obesity in humans [19] and rodents [20]. Generally, obesity leads to higher demand for insulin production and the same is met by increase in beta cell mass. Obesity is also a major risk factor for the onset of peripheral insulin resistance [21]. Insulin resistance leads to further higher demand for insulin from beta cells, and eventually triggering beta cell failure. This results in beta cell survival defects, insufficient beta cell mass and deterioration of the key beta cell function i.e. glucose stimulated insulin secretion, and ultimately type 2 diabetes. Thus, the mass of insulin producing beta cells changes dynamically according to the metabolic conditions [22,23]. Alternatively, obesity may be a consequence of higher insulin levels [24,25,26] as insulin has stimulatory effect on adipogenesis by increasing the lipid accumulation in adipocytes [27,28,29]. Insulin is also involved in adipocyte survival [30]. Adipose tissue-specific insulin receptor gene knockout protects against obesity, emphasizing that insulin signaling to adipocytes is important for development of obesity [28]. Hyper insulin secretion in MOR-1 opioid receptor knockout mice results in higher body weight [26] whereas CHOP knockout mice become obese with increasing insulin secretion although glucose tolerance remains unchanged in these mice [31]. PLoS ONE | www.plosone.org 1 June 2012 | Volume 7 | Issue 6 | e38685