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Alteration of murine Regulator of Calcineurin 1 (Rcan1) results in dysmorphogenesis of pancreatic islets
Author(s) -
Gurda Grzegorz,
Baras Alexander,
Williams John,
Cornish Toby
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.765.1
Subject(s) - medicine , endocrinology , islet , pancreas , glucagon , immunohistochemistry , pancreatic islets , insulin , genetically modified mouse , biology , transgene , biochemistry , gene
Background Regulator of Calcineurin 1 (Rcan1) overexpression recapitulates many traits of Down Syndrome (DS). Several neurologic deficits of DS are seen in Rcan1 transgenic mice (Rcan1 TG). Cardiac hypertrophy and immune dysregulation of DS are also seen in Rcan1 TG. Lastly, diabetes is also more prevalent in DS. Rcan1 restricts growth of exocrine pancreas; its role in islets remains poorly understood. Methods: Pancreatic tissue was obtained from Rcan1 +/+ controls, Rcan1 TG and Rcan1 KO mice. H&E slides were imaged and quantified. Immunohistochemistry (IHC) for insulin, glucagon and CD31 were performed and quantified. Results: By image analysis, Rcan1 TG had a significant (p<0.01) increase in number (192%), but a decrease in the avg size (35%) of islets vs controls. Islets as % total pancreas decreased (65% of Rcan1 +/+). In contrast, Rcan1 KO mice had variably sized, dysmorphic islets and an increase in islets as % total pancreas (135%, p<0.01). There was a trend (p=0.09) to larger islets in older/heavier mice and no difference in male vs female. The exocrine pancreas of Rcan1 TG and Rcan1 KO mice was unremarkable; in endocrine islets the relative number and distribution of insulin and glucagon by IHC was normal. By blinded review, the islets in 71% of Rcan1 KO mice exhibited < 3 dysmorphic features of human nesidioblastosis, a much higher rate than RCAN1 +/‐ (18%) or RCAN1 +/+ (6%), with good agreement (k=0.65) between 2 pathologists. Conclusion Rcan1 overexpresion increases the number but reduces the size of pancreatic islets. Rcan1 deficiency has the opposite effect, along with dysmorphogenesis that histologically mimics human nesidioblastosis.