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Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin.

Jiang Y, Nishimura W, Devor-Henneman D, Kusewitt D, Wang H, Holloway MP, Dohi T, Sabo E, Robinson ML, Altieri DC, Sharma A, Altura RA - Diabetes (2008)

Bottom Line: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-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 beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

ABSTRACT

Objective: Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-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 beta-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 beta-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 beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

Conclusions: Our findings implicate survivin in the maintenance of beta-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes.

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Survivin expression becomes gradually restricted to β-cells after birth. A: Survivin expression in pancreatic endocrine and exocrine cells from E15.5 to P21, assessed by immunofluorescent staining of pancreatic tissue isolated from wild-type mice, using antibodies to survivin, β-catenin, Isl1, insulin (Ins), glucagon (Gluc), and somatostatin (Som). Survivin is expressed throughout the pancreatic epithelium at E15.5 (β-catenin+, Isl1+ cells), becomes gradually restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (P14), and then is further restricted to β-cells (Ins+) by P21. Magnification ×20. Bar = 20 μm. B: Analysis of expression of differentiation markers in pancreatic sections isolated from Pax6-cre;survivinlox/lox mice and their littermate controls. Comparisons between mutant (MUT) and littermate controls (WT) indicated similar patterns and levels of expression at E15.5 and E19.5. Magnification ×20. Bar = 20 μm. (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
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f1: Survivin expression becomes gradually restricted to β-cells after birth. A: Survivin expression in pancreatic endocrine and exocrine cells from E15.5 to P21, assessed by immunofluorescent staining of pancreatic tissue isolated from wild-type mice, using antibodies to survivin, β-catenin, Isl1, insulin (Ins), glucagon (Gluc), and somatostatin (Som). Survivin is expressed throughout the pancreatic epithelium at E15.5 (β-catenin+, Isl1+ cells), becomes gradually restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (P14), and then is further restricted to β-cells (Ins+) by P21. Magnification ×20. Bar = 20 μm. B: Analysis of expression of differentiation markers in pancreatic sections isolated from Pax6-cre;survivinlox/lox mice and their littermate controls. Comparisons between mutant (MUT) and littermate controls (WT) indicated similar patterns and levels of expression at E15.5 and E19.5. Magnification ×20. Bar = 20 μm. (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)

Mentions: To gain insight into the regulatory potential of survivin in pancreatic β-cells, we determined its expression pattern in the mouse pancreas during normal embryonic development and after birth. Survivin protein was readily detected throughout the pancreatic epithelium, including endocrine cells during the secondary transition (E15.5), as shown by the cytoplasmic staining of survivin in cells that express β-catenin, insulin, and Isl1 (Fig. 1A). Survivin expression gradually became restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (postnatal day [P] 14) (Fig. 1A). By P21, one can detect several Isl1+ cells that do not express survivin, suggesting a further restriction of survivin expression to a subpopulation(s) of endocrine cells (Fig. 1A). Colocalization of survivin with insulin was also observed at these time points, with a relative lack of survivin staining within cells that stained positive for glucagon and somatostatin (Fig. 1A, panel 2), suggesting that survivin expression becomes restricted to β-cells by P21. Expression of survivin in mature, differentiated β-cells after birth was unexpected, because activation of this gene was previously reported only in undifferentiated and highly proliferating cells in the adult animal (26). Therefore, we confirmed the expression of survivin in these cells by isolating islets from normal mice at 1 and 2 weeks after birth and performing RT-PCR for survivin, insulin, and glyceraldehyde-3-phosphate dehydrogenase (supplementary Fig. 1A. The pattern of survivin expression within the pancreas is similar to the reported pattern of key transcription factors that contribute to β-cell development during embryogenesis and after birth, including Nkx6.1 and Pdx1 (5,33). It is possible that such factors may restrict survivin expression to β-cells during the postnatal period.


Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin.

Jiang Y, Nishimura W, Devor-Henneman D, Kusewitt D, Wang H, Holloway MP, Dohi T, Sabo E, Robinson ML, Altieri DC, Sharma A, Altura RA - Diabetes (2008)

Survivin expression becomes gradually restricted to β-cells after birth. A: Survivin expression in pancreatic endocrine and exocrine cells from E15.5 to P21, assessed by immunofluorescent staining of pancreatic tissue isolated from wild-type mice, using antibodies to survivin, β-catenin, Isl1, insulin (Ins), glucagon (Gluc), and somatostatin (Som). Survivin is expressed throughout the pancreatic epithelium at E15.5 (β-catenin+, Isl1+ cells), becomes gradually restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (P14), and then is further restricted to β-cells (Ins+) by P21. Magnification ×20. Bar = 20 μm. B: Analysis of expression of differentiation markers in pancreatic sections isolated from Pax6-cre;survivinlox/lox mice and their littermate controls. Comparisons between mutant (MUT) and littermate controls (WT) indicated similar patterns and levels of expression at E15.5 and E19.5. Magnification ×20. Bar = 20 μm. (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2551682&req=5

f1: Survivin expression becomes gradually restricted to β-cells after birth. A: Survivin expression in pancreatic endocrine and exocrine cells from E15.5 to P21, assessed by immunofluorescent staining of pancreatic tissue isolated from wild-type mice, using antibodies to survivin, β-catenin, Isl1, insulin (Ins), glucagon (Gluc), and somatostatin (Som). Survivin is expressed throughout the pancreatic epithelium at E15.5 (β-catenin+, Isl1+ cells), becomes gradually restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (P14), and then is further restricted to β-cells (Ins+) by P21. Magnification ×20. Bar = 20 μm. B: Analysis of expression of differentiation markers in pancreatic sections isolated from Pax6-cre;survivinlox/lox mice and their littermate controls. Comparisons between mutant (MUT) and littermate controls (WT) indicated similar patterns and levels of expression at E15.5 and E19.5. Magnification ×20. Bar = 20 μm. (Please see http://dx.doi.org/10.2337/db08-0170 for a high-quality digital representation of this image.)
Mentions: To gain insight into the regulatory potential of survivin in pancreatic β-cells, we determined its expression pattern in the mouse pancreas during normal embryonic development and after birth. Survivin protein was readily detected throughout the pancreatic epithelium, including endocrine cells during the secondary transition (E15.5), as shown by the cytoplasmic staining of survivin in cells that express β-catenin, insulin, and Isl1 (Fig. 1A). Survivin expression gradually became restricted to endocrine (Isl1+) cells in late embryogenesis (E19.5) and postnatally (postnatal day [P] 14) (Fig. 1A). By P21, one can detect several Isl1+ cells that do not express survivin, suggesting a further restriction of survivin expression to a subpopulation(s) of endocrine cells (Fig. 1A). Colocalization of survivin with insulin was also observed at these time points, with a relative lack of survivin staining within cells that stained positive for glucagon and somatostatin (Fig. 1A, panel 2), suggesting that survivin expression becomes restricted to β-cells by P21. Expression of survivin in mature, differentiated β-cells after birth was unexpected, because activation of this gene was previously reported only in undifferentiated and highly proliferating cells in the adult animal (26). Therefore, we confirmed the expression of survivin in these cells by isolating islets from normal mice at 1 and 2 weeks after birth and performing RT-PCR for survivin, insulin, and glyceraldehyde-3-phosphate dehydrogenase (supplementary Fig. 1A. The pattern of survivin expression within the pancreas is similar to the reported pattern of key transcription factors that contribute to β-cell development during embryogenesis and after birth, including Nkx6.1 and Pdx1 (5,33). It is possible that such factors may restrict survivin expression to β-cells during the postnatal period.

Bottom Line: Selective deletion of survivin in pancreatic endocrine cells in the mouse had no discernible effects during embryogenesis but was associated with striking decreases in beta-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 beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

ABSTRACT

Objective: Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-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 beta-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 beta-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 beta-cells lacking endogenous survivin completely rescued the hyperglycemic phenotype and the decrease in beta-cell mass, confirming the specificity of the survivin effect in these cells.

Conclusions: Our findings implicate survivin in the maintenance of beta-cell mass through both replication and antiapoptotic mechanisms. Given the widespread involvement of survivin in cancer, a novel role for survivin may well be exploited in beta-cell regulation in diseased states, such as diabetes.

Show MeSH
Related in: MedlinePlus