The diabetes gene <i>Hhex</i> maintains δ-cell differentiation and islet function

Zhang, Jia; McKenna, Lindsay B.; Bogue, Clifford W.; Kaestner, Klaus H.

doi:10.1101/gad.235499.113

Cited by 119 publications

(125 citation statements)

References 33 publications

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“…Surprisingly, mRNAs encoding all pancreatic hormones, including ghrelin, gastrin, glucagon, somatostatin, and pancreatic polypeptide, were upregulated in PAX6-deficient cells (even though only ghrelin could be detected at the protein level; Figure 4B and Supplemental Figure 5). We also observed upregulation of multiple TFs (Supplemental Table 2), including some known regulators of non-β cell programs, such as Hhex (a direct activator of somatostatin transcription) (42).…”

Section: Resultsmentioning

confidence: 94%

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

Swisa¹,

Avrahami²,

Eden³

et al. 2016

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 94%

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

Swisa¹,

Avrahami²,

Eden³

et al. 2016

Journal of Clinical Investigation

Self Cite

130

142

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“…Moreover, we observed that Cav1.2 expression was specifically regulated in pancreatic δ cells, but not in pancreatic β cells, owing to selective HHEX interactions ( Figure 6, J-M). The diabetes gene Hhex is specifically expressed in pancreatic δ cells and is important for δ cell differentiation (11). In TGP52 cells, HHEX associates with the CRL4B-PRC2 complex Figure 9.…”

Section: Discussionmentioning

confidence: 99%

“…The disruption of this fine-tuned islet circuit by the aberrant regulation of paracrine islet interactions plays an important role in the development of diabetes (1)(2)(3)(4)(5)(6)(7)(8)(9). For example, the loss of the important paracrine factor urocortin 3 (UCN3) in pancreatic β cells caused dysregulation of a somatostatin-mediated negative feedback loop between islet δ and β cells, resulting in aberrant glucoseinduced insulin secretion and contributing to the pathophysiology of diabetes (5,10,11). Recently, the functional importance of pancreatic δ cells in maintaining glucose homeostasis is increasingly being appreciated.…”

Section: Introductionmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B)Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 6 3 3 jci.orgVolume 127 Number 7 July 2017mental Figure 1E). Immunofluorescence also showed no significant differences in islet or β or δ cell numbers between +/-mice, the knockout mice exhibited increased glucose levels after 2 hours of feeding following a 16-hour fast ( Figure 1G). Accordingly, during a glucose tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice were 33% and 30% higher at 30 minutes and 120 minutes, respectively, than those of the control group consisting of both Sst-Cre +/-and Cul4b fl/Y mice ( Figure 1H). In addition, during the insulin tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice unexpectedly decreased more dramatically and rapidly than those of the Sst-Cre +/-control mice in response to insulin stimulation ( Figure 1I). Insulin and somatostatin content as well as kidney, brain, heart, liver, and stomach weights were not found to be significantly different between the mice was 140% and 40% higher than that of Sst-Cre +/-mice at 5 minutes and 60 minutes, respectively ( Figure 2H). In contrast to the results found for the Sst-Cre +/-Cul4b fl/Y mice, CUL4B defistrated that CRL4 ubiquitinates WD repeat-containing protein 5 (WDR5), a core subunit of H3K4 methyltransferase complexes, for degradation in the nucleus, thereby promoting increased H3K4 methylation levels (30). However, whether CUL4B or its E3 ligase complex CRL4B-PRC2 participates in the functioning or development of Langerhans islets has not been studied. In this study, we found that CUL4B expression levels are decreased in db/db mice. Therefore, we crossed mice expressing Cre under the insulin II promotor (Ins2-Cre) and mice expressing Cre under the somatostatin promoter (Sst-Cre) with Cul4b fl/fl mice to characterize CUL4B functions in specific cell types of the islet circuit. Although In...

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“…There are limited mature δ-cell markers, and the β-cell-derived δ-like cells all expressed Hhex (Zhang et al, 2014) and somatostatin (Fig. S5F).…”

Section: The Massively Increased δ/δ-Like Cell Number In Mnx1mentioning

confidence: 99%

“…7I). Recent studies from Zhang et al (2014) demonstrated that loss of Hhex in endocrine progenitors and adult δ-cells led to a complete loss of δ-cells, indicating that Hhex is a principal determinant of δ-cell fate during endocrine lineage allocation and postnatal δ-cell fate maintenance. Prior studies in Drosophila and mouse reported that Mnx1, via its tinman repressor domain, acts predominantly as a repressor in neuron subtype determination (Broihier and Skeath, 2002;William et al, 2003;Lacin et al, 2014).…”

Section: Mnx1 As a β-Cell Lineage-allocation Factormentioning

confidence: 99%

Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells

et al. 2015

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Homozygous Mnx1 mutation causes permanent neonatal diabetes in humans, but via unknown mechanisms. Our systematic and longitudinal analysis of Mnx1 function during murine pancreas organogenesis and into the adult uncovered novel stage-specific roles for Mnx1 in endocrine lineage allocation and β-cell fate maintenance. Inactivation in the endocrine-progenitor stage shows that Mnx1 promotes β-cell while suppressing δ-cell differentiation programs, and is crucial for postnatal β-cell fate maintenance. Inactivating Mnx1 in embryonic β-cells (Mnx1 Δbeta ) caused β-to-δ-like cell transdifferentiation, which was delayed until postnatal stages. In the latter context, β-cells escaping Mnx1 inactivation unexpectedly upregulated Mnx1 expression and underwent an age-independent persistent proliferation. Escaper β-cells restored, but then eventually surpassed, the normal pancreatic β-cell mass, leading to islet hyperplasia in aged mice. In vitro analysis of islets isolated from Mnx1Δbeta mice showed higher insulin secretory activity and greater insulin mRNA content than in wild-type islets. Mnx1 Δbeta mice also showed a much faster return to euglycemia after β-cell ablation, suggesting that the new β-cells derived from the escaper population are functional. Our findings identify Mnx1 as an important factor in β-cell differentiation and proliferation, with the potential for targeting to increase the number of endogenous β-cells for diabetes therapy.

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The diabetes gene Hhex maintains δ-cell differentiation and islet function

Cited by 119 publications

References 33 publications

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

PAX6 maintains β cell identity by repressing genes of alternative islet cell types

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a δ-like fate and reveals a facultative proliferative capacity in aged β-cells

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