Notch signaling dynamically regulates adult β cell proliferation and maturity

Bartolomé, Alberto; Zhu, Changyu; Sussel, Lori; Pajvani, Utpal B.

doi:10.1172/jci98098

Cited by 48 publications

(57 citation statements)

References 62 publications

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“…Recently, it has been reported that mice given β-cell specific Notch gain of function (β-NICD) in adult stage had increased β-cell proliferative capacity but a progressive loss of β-cell maturity. In this study, chronic Notch activity in β-cell induced β-cell proliferation without maturation [15]. Although the methods used in the previous study differed from those of our study, the previous results were similar to those of the present study.…”

Section: Discussionsupporting

confidence: 85%

Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

et al. 2021

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Background: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). Methods: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. Results: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 μm) decreased while that of small islets (<250 μm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. Conclusion: Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and β-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in β-cell mass determination and diabetes.

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Section: Discussionsupporting

confidence: 85%

Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

et al. 2021

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“…A loss of function of these genes is associated with a loss of mature function accompanied by a fetal/immature gene expression phenotype with expression of disallowed genes with high MafB expression and loss of MafA expression. In contrast to this de-differentiation phenotype, that is seen in many adult β-cell proliferative phenotypes, such as with activation of c-Myc (Puri et al, 2018) or Notch (Bartolome et al, 2019), loss of Tead1 function is not associated with re-expression of many of the disallowed genes, such as Ldha, nor a re-expression of MafB, markers of immature mouse β-cells (Nishimura et al, 2006). Interestingly a change in methylation status of the promoters of the genes has been associated with acquisition of mature β-cell function, specifically demethylation of the promoters of genes associated with maintenance of mature β-cell function and methylation of disallowed gene promoters (Dhawan et al, 2015).…”

Section: Discussionmentioning

confidence: 96%

Tead1 reciprocally regulates adult β-cell proliferation and function to maintain glucose homeostasis

Lee

Liu

Kim

et al. 2020

Preprint

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Diabetes ensues when there is a net decrease in functional β-cell mass. Efforts to increase β-cell mass are limited by a concurrent loss of mature function. The molecular mechanisms underlying the reciprocal regulation between β-cell proliferation and mature function are unclear. Here, we demonstrate that constitutive and inducible genetic deletion of Tead1 in mouse β-cells leads to diabetes. Tead1, the transcription factor downstream of the mammalianhippo pathway, has a developmental stage-specific critical function in β-cells and is required for maintenance of mature β-cell functional competence by direct transcriptional regulation of a network of critical β-cell transcription factors, including, Pdx1, Nkx6.1 and MafA. Concurrently, Tead1 directly activates Cdkn2a transcription in adult β-cells to inhibit proliferation. Studies in human β-cells demonstrate that Tead1 plays a similar regulatory role. Taken together, our findings uncover the non-redundant role of Tead1 in modulating the balance between proliferative capacity and functional competence.

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“…However, the effect is dependent on the cell type. For instance, adult β cell proliferation and maturity were dynamically regulated by Notch signaling (Bartolome, Zhu, Sussel, & Pajvani, ). In endothelial cells, Notch signaling regulates contact inhibition and cycle arrest (Noseda et al, ).…”

Section: Discussionmentioning

confidence: 99%

Notch signaling inhibition induces G0/G1 arrest in murine Leydig cells

Feng

Wen

et al. 2019

Andrologia

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As a highly evolutionarily conserved signaling pathway, Notch widely participates in cell-fate decisions and the development of various tissues and organs. In male reproduction, research on the Notch signaling pathway has mainly concentrated on germ cells and Sertoli cells. Leydig cells are the primary producers of testosterone and play important roles in spermatogenesis and maintaining secondary sexual characteristics. In this study, we used TM3 cells, a murine adult Leydig cell line, to investigate the expression profiles of Notch receptors and ligands and observe the effect of Notch signaling on the proliferation of TM3 cells. We found that Notch 1-3 and the ligands Dll-1 and Dll-4 were expressed in TM3 cells, Notch 1-3 and the ligand Dll-1 were expressed in testis interstitial Leydig cells, and Notch signaling inhibition suppressed the proliferation of TM3 cells and induced G0/G1 arrest. Inhibition of Notch signaling increased the expression of p21 Waf1/Cip1 and p27. Overall, our results suggest that Notch inhibition suppresses the proliferation of TM3 cells and P21 Waf1/Cip1 , and p27 may contribute to this process. K E Y W O R D Scell proliferation, Leydig cell, P21 Waf1/Cip1 , P27

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Notch signaling dynamically regulates adult β cell proliferation and maturity

Cited by 48 publications

References 62 publications

Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes

Tead1 reciprocally regulates adult β-cell proliferation and function to maintain glucose homeostasis

Notch signaling inhibition induces G0/G1 arrest in murine Leydig cells

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