Survivin Regulation of Beta-Cell Mass Expansion Figure 6. Islet development in RIPcre+survivinfl/fl mice and controls after PDL. (a) In day 7 PDL pancreas, insulin and glucagon positive cells show abnormal distribution in the mutant mice (upper panel, original magnification, 6400). Quantification reveals that the knockout islet has a markedly higher proportion of alpha cells to beta cells as compared with controls (lowerleft panel). But alpha cell mass is similar in the two groups (lower right panel) (n = 5 per genotype). (b) Fold change in the expression of the indicated genes related to islet neogenesis as determined by quatitative PCR are similar in day 7 PDL pancreas in the mutant mice (gray bars) compared with controls (black bars) (n = 5 per genotype). WT, wildtype; KO, knockout. The data represent as means 6 SE. **p,0.01 vs control. doi:10.1371/journal.pone.0041976.g006 beta cells stimulated by 60% partial pancreatectomy (PPx) [28]. Survivin, as the known FoxM1 target, was the most significantly upregulated gene during the peak of beta-cell proliferation following PPx. Given the multi-regulatory role of survivin in the various cellular processes, our result demonstrated that survivin was required for injury-stimulated beta-cell proliferation in adult mice. To dissect the physiological role of survivin in beta-cell mass expansion, we generated RIP-driven survivin knockout mice. Because of the lack of survivin expression during embryonic development and neonatal period, the mutant mice exhibited a decreased beta-cell mass at 2-month of age compared to wildtype littermate controls. The male mutant mice displayed glucose intolerance whereas the female mutant mice remained glucose tolerant despite the reduced beta-cell mass. This phenomenon has been observed in other rodent models of diabetes [29–31] and has been linked to a protective effect of estrogen [32,33]. We took advantage of this finding and focused on female mice, as this PLoS ONE | www.plosone.org 8 August 2012 | Volume 7 | Issue 8 | e41976