Neurogenin 3–Directed Cre Deletion of Tsc1 Gene Causes Pancreatic Acinar Carcinoma

Ding, Li; Han, Lingling; Li, Yin; Zhao, Jing; He, Ping; Zhang, Weizhen

doi:10.1016/j.neo.2014.08.010

Cited by 16 publications

(21 citation statements)

References 37 publications

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“…Ngn3-Cre mice that express the Cre recombinase gene under the control of the Ngn3 gene promoter, as well as Tsc1 loxP/loxP mice, in which exons 17 and 18 of the Tsc1 gene are flanked by loxP sites by homologous recombination, were purchased from the Jackson Laboratory. The Negn3-Tsc1−/− mice were generated by breeding Tsc1 loxP/loxP mice with Ngn3-Cre mice as described previously (Ding et al 2014, Xu et al 2015. Control experiments used littermate Tsc1 loxP/loxP animals.…”

Section: Animals and Animal Carementioning

confidence: 99%

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TSC1-mTOR signaling determines the differentiation of islet cells

Ding

Yin

Han

et al. 2017

Journal of Endocrinology

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Neurogenin3-driven deletion of tuberous sclerosis complex 1 (Tsc1) activated mechanistic target of rapamycin complex 1 (mTORC1) measured by the upregulation of mTOR and S6 phosphorylation in islet cells. Neurogenin3-Tsc1-/- mice demonstrated a significant increase in average islet size and mean area of individual islet cell. Insulin mRNA and plasma insulin levels increased significantly after weaning. Glucagon mRNA and plasma levels increased in neonate followed by modest reduction in adult. Somatostatin mRNA and plasma levels markedly increased. Neurogenin3-Tsc1-/- mice fed standard chow demonstrated a significant improvement in glucose tolerance and no alteration in insulin sensitivity. In Neurogenin3-Tsc1-/- mice fed 45% high-fat diets, both glucose tolerance and insulin sensitivity were significantly impaired. Rapamycin reversed the activation of mTORC1, attenuated β cells hypertrophy and abolished the improvement of glucose tolerance. TSC1-mTORC1 signaling plays an important role in the development of pancreatic endocrine cells and in the regulation of glucose metabolism.

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Section: Animals and Animal Carementioning

confidence: 99%

“…Genomic DNA was extracted from tail cuttings. Polymerase chain reactions were performed to test for the presence of the Tsc1 and/or the deletion of its exons 17 and 18 using LoxP primers, and Cre constructs using cre-specific primers, respectively (Ding et al 2014, Xu et al 2015.…”

Section: Genotypingmentioning

confidence: 99%

TSC1-mTOR signaling determines the differentiation of islet cells

Ding

Yin

Han

et al. 2017

Journal of Endocrinology

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“…The embryonic pancreas development is regulated by the interactions of numerous signaling pathways that contribute to the proper initiation of the sequential expression of transcription factors (22)(23)(24)(25). Several transcription factors have been demonstrated to be necessary for the development of a functional pancreas, including Pdx1, Ngn3 and MafA.…”

Section: Discussionmentioning

confidence: 99%

Pax4 synergistically acts with Pdx1, Ngn3 and MafA to induce HuMSCs to differentiate into functional pancreatic β‑cells

Zhang

Wang

et al. 2019

Exp Ther Med

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It has been indicated that the combination of pancreatic and duodenal homeobox 1 (Pdx1), MAF bZIP transcription factor A (MafA) and neurogenin 3 (Ngn3) was able to reprogram various cell types towards pancreatic β-like cells (pβLCs). Paired box 4 (Pax4), a transcription factor, has a key role in regulating the maturation of pancreatic β-cells (pβCs). In the present study, it was investigated whether Pax4 is able to synergistically act with Pdx1, Ngn3 and MafA to induce human umbilical cord mesenchymal stem cells (HuMSCs) to differentiate into functional pβCs in vitro. HuMSCs were isolated, cultured and separately transfected with adenovirus (Ad) expressing enhanced green fluorescence protein, Pax4 (Ad-Pax4), Pdx1+MafA+Ngn3 (Ad-3F) or Ad-Pxa4 + Ad-3F. The expression of C-peptide, insulin and glucagon was detected by immunofluorescence. The transcription of a panel of genes was determined by reverse transcription-quantitative PCR, including glucagon (GCG), insulin (INS), NK6 homeobox 1 (NKX6-1), solute carrier family 2 member 2 (SLC2A2), glucokinase (GCK), proprotein convertase subtilisin/kexin type 1 (PCSK1), neuronal differentiation 1 (NEUROD1), ISL LIM homeobox 1 (ISL 1), Pax6 and PCSK type 2 (PCSK2). Insulin secretion stimulated by glucose was determined using ELISA. The results suggested that, compared with Ad-3F alone, cells co-transfected with Ad-Pax4 and Ad-3F expressed higher levels of INS and C-peptide, as well as genes expressed in pancreatic β precursor cells, and secreted more insulin in response to high glucose. Furthermore, the expression of GCG in cells transfected with Ad-3F was depressed by Ad-Pax4. The present study demonstrated that Pax4 was able to synergistically act with the transcription factors Pdx1, Ngn3 and MafA to convert HuMSCs to functional pβLCs. HuMSCs may be potential seed cells for generating functional pβLCs in the therapy of diabetes.

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“…37 The NEUROG3 transcription factor is expressed in neuroendocrine prostate tumors and invasive neuroendocrine cancer, 38 and has been associated with the development of pancreatic acinar carcinoma. 39 In addition, induced inhibition of Neurog3 in mice has been found to impair differentiation of spermatogonial stem cells into progenitor cells 40 ; it is possible that this also could be the case for other types of stem cells. The rs4536103 minor allele (G) results in a missense mutation (Phe to Ser).…”

Section: Maternal Genotype and Childhood All/archer Et Almentioning

confidence: 99%

Family‐based exome‐wide assessment of maternal genetic effects on susceptibility to childhood B‐cell acute lymphoblastic leukemia in hispanics

Archer¹,

Pérez-Andreu

Scheurer

et al. 2016

Cancer

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Background Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other ethnic groups, but the genetic basis for racial disparities remain incompletely understood. Genome-wide association studies (GWAS) of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on offspring phenotype development) may also play a role in ALL susceptibility. Methods We conducted a family-based exome-wide association study (EXWAS) of maternal genetic effects among Hispanics with childhood B-cell ALL (B-ALL) using the Illumina Human Exome BeadChip. We used a discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families. Results Three maternal SNPs approached our threshold for significance, after correction for multiple testing (P<1.0×10−6): MTL5 rs12365708 (RR=2.62, 95% CI=1.61-4.27, P=1.8×10−5); ALKBH1 rs6494 (RR=3.77, 95% CI=1.84-7.74, P=3.7×10−5); NEUROG3 rs4536103 (RR=1.75, 95% CI=1.30-2.37, P=1.2×10−4). While effect sizes were similar, these SNPs were not nominally significant in our replication cohort. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not statistically significant after correction for multiple comparisons (rs12365708: pooled RR=2.27, 95% CI=1.48-3.50, P=1.99×10−4; rs6494: pooled RR=2.31, 95% CI=1.38-3.85, P=0.001; rs4536103: pooled RR=1.67, 95% CI=1.29-2.16, P=9.23×10−5). Conclusions In the first family-based EXWAS to investigate maternal genotype effects associated with childhood ALL, our results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, we identified three maternal SNPs that may play a modest role in susceptibility.

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Neurogenin 3–Directed Cre Deletion of Tsc1 Gene Causes Pancreatic Acinar Carcinoma

Cited by 16 publications

References 37 publications

TSC1-mTOR signaling determines the differentiation of islet cells

TSC1-mTOR signaling determines the differentiation of islet cells

Pax4 synergistically acts with Pdx1, Ngn3 and MafA to induce HuMSCs to differentiate into functional pancreatic β‑cells

Family‐based exome‐wide assessment of maternal genetic effects on susceptibility to childhood B‐cell acute lymphoblastic leukemia in hispanics

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