Expression of Cholecystokinin in the Pancreas During Development

Shimizu, Kyoko; Shiratori, Keiko; Sakayori, Noriko; Kobayashi, M.; Hayashi, Nariyuki

doi:10.1097/00006676-199907000-00015

Cited by 7 publications

(5 citation statements)

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“…1A). The NPG cell population represented 4.3% Ϯ 0.1% of the total endocrine cell number at postnatal day 0 (P0) but became undetectable at P7 (data not shown), consistent with previous results reported in the literature (17,29). We noticed that in the normal adult mouse pancreas, weak expression of both gastrin and progastrin was detected in alpha cells with one of the antigastrin antibodies used in this study (SCBT) (see Fig.…”

Section: Pancreatic Gastrinsupporting

confidence: 92%

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

Bonnavion

Teinturier

Jaafar

et al. 2015

Molecular and Cellular Biology

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The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a ؉ and neurogenin 3-expressing (Ngn3 ؉ ) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors. G astrinomas are endocrine tumors which secrete the peptide hormone gastrin. They cause Zollinger-Ellison syndrome (ZES), characterized by multiple duodenal-jejunal ulcers, diarrhea, and gastroesophageal reflux (1). Most gastrin-producing cells are found in the adult gastric antrum and, to a lesser extent, in the proximal duodenum in mammals. Intriguingly, most primary gastrinomas are found in the duodenum. The rest are mainly in the pancreas and are only rarely found in the stomach and elsewhere (liver, lung, and ovaries) (2). Gastrinomas develop either sporadically or hereditarily, as seen in patients with multiple endocrine neoplasia type 1 (MEN1; disease identifier OMIM131100). MEN1 patients develop multiple tumors in endocrine organs, primarily affecting parathyroid glands, the pituitary, the pancreas, and the foregut. Gastrinomas are the most common functioning tumors of the gastroenteropancreatic axis in MEN1 patients (3, 4), displaying multiple small lesions in the duodenum and, in rare cases, in the pancreas. Sporadic gastrinomas are often solitary tumors occurring both in the duodenum and in the pancreas, and the etiology is poorly understood. Interestingly, somatic MEN1 mutations and a loss of heterozygosity at the MEN1 locus have been detected in approximately 30% of both sporadic duodenal and pancreatic gastrinomas (5, 6). In addition, we have previously reported gastrin-expressing pancreatic tumors in about 15% of heterozygous Men1 mutant mice (7), confirming that M...

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Section: Pancreatic Gastrinsupporting

confidence: 92%

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

Bonnavion

Teinturier

Jaafar

et al. 2015

Molecular and Cellular Biology

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“…Notably, Gast expression was not detected in various models of mouse β cell dedifferentiation, such as in the context of Aldh1a3 + cells ( 20 ) or a vitamin D–binding protein (DBP) in a model of multiparity-induced diabetes ( 22 ) mice. Collectively, these results suggest that MafA represses postnatal production of hormones that are normally only transiently expressed during pancreatic β cell development and predominately elsewhere in the adult, such as Gast (duodenum, stomach) ( 9 ) and Cck (small intestine) ( 23 ). These data further indicate that MafA deficiency not only compromises adult mouse β cell activity but also β cell identity rather than dedifferentiation.…”

Section: Resultsmentioning

confidence: 89%

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

Cha,

Tong,

Walker

et al. 2023

JCI Insight

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Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet β cells, characterized by inappropriate production of other islet cell–enriched hormones. Here, we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin + (Gast + ) cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a GAST + gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repress GAST gene transcription. These results support a potentially novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively. Here, we discuss the possibility that induction of Gast/GAST and other non–β cell hormones, by reduction in the levels of these transcription factors, represents a dysfunctional β cell signature.

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“…However, gene markers associated with β cell dedifferentiation, such as Ngn3, FoxO1 , and Aldh1a3 (19, 20), were not detectable in MafA Δβ or control β cells in either sex (data not shown). Collectively, these results suggest that MafA can repress production of hormones that are normally only transiently expressed during pancreatic β cell development and predominately made elsewhere postnatally, such as Gast (duodenum, stomach) (8) and Cck (small intestine) (21).…”

Section: Resultsmentioning

confidence: 89%

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

Cha

Tong

Walker

et al. 2022

Preprint

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Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (β) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repressGASTgene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively, by repressing expression of Gast/GAST and other non-β cell hormones.

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Expression of Cholecystokinin in the Pancreas During Development

Cited by 7 publications

References 0 publications

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

Species-specific roles for the MAFA and MAFB transcription factors in regulating islet β cell identity

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