Phenotypes associated with this allele

• Allele Symbol: Ier3ip1^tm1Arvn
• Allele Name: targeted mutation 1, Peter Arvan
• Allele ID: MGI:7578873
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Ier3ip1^tm1Arvn/Ier3ip1^tm1Arvn Tg(Ins1-cre/ERT)1Lphi/0	involves: 129S4/SvJaeSor * C57BL/6J * CD-1	MGI:7620431
cn2	Ier3ip1^tm1Arvn/Ier3ip1^tm1Arvn Tg(Ins2-cre)25Mgn/0	involves: C57BL/6 * C57BL/6J * DBA	MGI:7620429

Genotype
MGI:7620431

cn1

• Allelic Composition: Ier3ip1^tm1Arvn/Ier3ip1^tm1Arvn; Tg(Ins1-cre/ERT)1Lphi/0
• Genetic Background: involves: 129S4/SvJaeSor * C57BL/6J * CD-1

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

abnormal glucose homeostasis ( J:336782 )

♂ • male mice treated with tamoxifen at 8 weeks of age (to induce IER3IP1 deletion in beta cells in early adulthood) develop a diabetic phenotype

decreased insulin secretion ( J:336782 )

♂ • adult male mice show a reduction of proinsulin and insulin content in pancreatic islets at 2 and 4 weeks after tamoxifen injection

hyperglycemia ( J:336782 )

♂ • adult mice show persistent hyperglycemia at 4 weeks after tamoxifen injection

decreased circulating insulin level ( J:336782 )

♂ • adult mice show decreased serum insulin levels at 4 weeks after tamoxifen injection

impaired glucose tolerance ( J:336782 )

♂ • adult mice show significantly higher blood glucose levels than control littermates at all time points tested in oral glucose tolerance tests starting from 2 weeks after tamoxifen injection

endocrine/exocrine glands

increased pancreatic beta cell apoptosis ( J:336782 )

♂ • pancreatic islets show significantly increased mRNA levels of Trib3 (a mediator of ER stress-induced cell death) at 4 weeks after tamoxifen injection

♂ • in contrast, mRNA levels of the antiapoptotic gene Bcl2 are significantly suppressed

decreased pancreatic beta cell proliferation ( J:336782 )

♂ • pancreatic islets show significantly increased mRNA levels of the cell growth inhibitor p21/Cdkn1a at 4 weeks after tamoxifen injection

abnormal pancreatic beta cell morphology ( J:336782 )

♂ • adult male mice show a more-diffuse cytoplasmic distribution of proinsulin and increased Pro+/Ins-cells at 4 weeks after tamoxifen injection

abnormal pancreatic beta cell differentiation ( J:336782 )

♂ • pancreatic islets of adult male mice show significantly reduced mRNA levels of beta-cell transcription factors both at 2 weeks (Mafa) and at 4 weeks (Mafa, Pdx1, and Nkx6-1) after tamoxifen injection, along with decreases in PDX1 and NKX6-1 protein levels at 4 weeks post-injection

decreased insulin secretion ( J:336782 )

♂ • adult male mice show a reduction of proinsulin and insulin content in pancreatic islets at 2 and 4 weeks after tamoxifen injection

cellular

increased pancreatic beta cell apoptosis ( J:336782 )

♂ • pancreatic islets show significantly increased mRNA levels of Trib3 (a mediator of ER stress-induced cell death) at 4 weeks after tamoxifen injection

♂ • in contrast, mRNA levels of the antiapoptotic gene Bcl2 are significantly suppressed

abnormal pancreatic beta cell differentiation ( J:336782 )

♂ • pancreatic islets of adult male mice show significantly reduced mRNA levels of beta-cell transcription factors both at 2 weeks (Mafa) and at 4 weeks (Mafa, Pdx1, and Nkx6-1) after tamoxifen injection, along with decreases in PDX1 and NKX6-1 protein levels at 4 weeks post-injection

decreased pancreatic beta cell proliferation ( J:336782 )

♂ • pancreatic islets show significantly increased mRNA levels of the cell growth inhibitor p21/Cdkn1a at 4 weeks after tamoxifen injection

Genotype
MGI:7620429

cn2

• Allelic Composition: Ier3ip1^tm1Arvn/Ier3ip1^tm1Arvn; Tg(Ins2-cre)25Mgn/0
• Genetic Background: involves: C57BL/6 * C57BL/6J * DBA

growth/size/body

decreased body weight ( J:336782 )

• mice show a trend towards decreased body weight during the first 14 days of life

slow postnatal weight gain ( J:336782 )

• mice show impaired body weight gain starting from 11 weeks of age in male mice and 3 weeks of age in female mice

homeostasis/metabolism

abnormal glucose homeostasis ( J:336782 )

• both male and female mice develop early-onset insulin-deficient diabetes that becomes more severe at 3 weeks of age

decreased insulin secretion ( J:336782 )

• 3-wk-old mice show a significant reduction of proinsulin and insulin content in pancreatic islets

• absolute amount of secreted insulin in basal and glucose-stimulated conditions is dramatically reduced in proportion to the reduced insulin content

• however, glucose-stimulated proinsulin synthesis and glucose-stimulated insulin secretion (GSIS) are preserved

increased circulating glucose level ( J:336782 )

• mice exhibit a modest increase in blood glucose during the first 14 days of life

increased fasting circulating glucose level ( J:336782 )

• male and female mice show significantly higher fasting blood glucose levels than control littermates up to 16 weeks of age

hyperglycemia ( J:336782 )

• hyperglycemia progressively worsens over an observation period of 16 weeks

decreased circulating insulin level ( J:336782 )

• 3-wk-old male and female mice exhibit significantly lower fasting serum insulin levels than control littermates

impaired glucose tolerance ( J:336782 )

• 3-wk-old male and female mice exhibit significantly higher blood glucose levels than control littermates at all time points tested in oral glucose tolerance tests

endocrine/exocrine glands

increased pancreatic beta cell apoptosis ( J:336782 )

• pancreatic islets of 3-wk-old mice show significantly increased mRNA levels of Trib3 (a mediator of ER stress-induced cell death), along with a marked increase in nuclear chromatin condensation

• in contrast, mRNA levels of antiapoptotic genes (Bcl2l1 and Mcl1) are significantly suppressed

decreased pancreatic beta cell proliferation ( J:336782 )

• GO analyses of RNA-seq data show significant downregulation of biological pathways associated with cell proliferation in pancreatic islets from 3-wk-old mice

• Cdk1 (a core protein of the cell cycle) is significantly downregulated while immunostaining for Ki67 (a nuclear replication marker) is significantly reduced, suggesting decreased beta-cell proliferation

• in contrast, mRNA levels of cell growth inhibitors p21/Cdkn1a and p16/Cdkn2a are significantly upregulated

abnormal pancreatic beta cell morphology ( J:336782 )

• pancreatic beta cells of 3-wk-old mice show markedly dilated endoplasmic reticulum (ER) along with a significantly decreased insulin secretory granule number

• proinsulin is more diffusely distributed throughout the cytoplasm, unlike in wild-type beta cells where proinsulin is mostly localized in the juxtanuclear region

• ratio of proinsulin-positive/insulin-negative (Pro+Ins-) cells to total proinsulin positive (Pro+) cells is significantly increased, suggesting defective anterograde trafficking of proinsulin

abnormal pancreatic beta cell differentiation ( J:336782 )

• pancreatic islets of 3-wk-old mice show significantly reduced mRNA levels of key beta-cell transcription factors (Mafa, Pdx1, and Nkx6-1), along with significant decreases in PDX1 and NKX6-1 protein levels

• mRNA levels of Mafa and Pdx1 are decreased as early as at 2 weeks of age (before development of overt diabetes)

• islets show a significant increase in the abundance and intra-islet localization of glucagon+ cells as well as somatostatin+ cells along with a reduction in insulin+ cells, in addition to an increase in insulin+/glucagon+ double-positive cells and insulin+/somatostatin+ double-positive cells, indicating impaired beta-cell maturation and identity

decreased pancreatic beta cell mass ( J:336782 )

• pancreatic islets of 3-wk-old mice show a significant reduction in beta cell mass relative to control islets

small pancreatic islets ( J:336782 )

• pancreatic islets of 3-wk-old mice show a significant reduction in mean islet area relative to control islets

decreased insulin secretion ( J:336782 )

• 3-wk-old mice show a significant reduction of proinsulin and insulin content in pancreatic islets

• absolute amount of secreted insulin in basal and glucose-stimulated conditions is dramatically reduced in proportion to the reduced insulin content

• however, glucose-stimulated proinsulin synthesis and glucose-stimulated insulin secretion (GSIS) are preserved

cellular

abnormal endoplasmic reticulum morphology ( J:336782 )

• pancreatic beta cells show markedly dilated ER

increased pancreatic beta cell apoptosis ( J:336782 )

• pancreatic islets of 3-wk-old mice show significantly increased mRNA levels of Trib3 (a mediator of ER stress-induced cell death), along with a marked increase in nuclear chromatin condensation

• in contrast, mRNA levels of antiapoptotic genes (Bcl2l1 and Mcl1) are significantly suppressed

abnormal pancreatic beta cell differentiation ( J:336782 )

• pancreatic islets of 3-wk-old mice show significantly reduced mRNA levels of key beta-cell transcription factors (Mafa, Pdx1, and Nkx6-1), along with significant decreases in PDX1 and NKX6-1 protein levels

• mRNA levels of Mafa and Pdx1 are decreased as early as at 2 weeks of age (before development of overt diabetes)

• islets show a significant increase in the abundance and intra-islet localization of glucagon+ cells as well as somatostatin+ cells along with a reduction in insulin+ cells, in addition to an increase in insulin+/glucagon+ double-positive cells and insulin+/somatostatin+ double-positive cells, indicating impaired beta-cell maturation and identity

decreased pancreatic beta cell proliferation ( J:336782 )

• GO analyses of RNA-seq data show significant downregulation of biological pathways associated with cell proliferation in pancreatic islets from 3-wk-old mice

• Cdk1 (a core protein of the cell cycle) is significantly downregulated while immunostaining for Ki67 (a nuclear replication marker) is significantly reduced, suggesting decreased beta-cell proliferation

• in contrast, mRNA levels of cell growth inhibitors p21/Cdkn1a and p16/Cdkn2a are significantly upregulated

abnormal endoplasmic reticulum physiology ( J:336782 )

• pancreatic islets of 3-wk-old mice show impaired oxidative folding of proinsulin in the ER, as shown by markedly increased intermolecular disulfide-linked complexes (dimers, trimers, and high-molecular-weight proinsulin-associated complexes) under non-reducing conditions

increased endoplasmic reticulum stress ( J:336782 )

• pancreatic islets of 3-wk-old mice show a significant increase in both mRNA and protein levels of Hspa5 (aka BiP), along with a marked increase in protein levels of DNAJC3 (aka P58IPK), suggesting induced ER stress

• islets of 14- to 16-wk-old severely diabetic mice show significantly increased mRNA levels of ER stress markers (Hspa5 and Dnajc3)

• however, among genes involved in the unfolded protein response (UPR), only expression of Eif2ak3 (aka PERK) is moderately increased in severely diabetic mice, suggesting only a modest activation of UPR in beta cells