The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses Beta- to Delta-Cell Transdifferentiation

The allocation and specification of pancreatic endocrine lineages are tightly regulated by transcription factors. Disturbances in differentiation of these lineages contribute to the development of various metabolic diseases, including diabetes. The Insulinoma-associated protein 1 (Insm1), which encodes a protein containing one SNAG domain and five zinc fingers, plays essential roles in pancreatic endocrine cell differentiation and in mature beta-cell function. In the present study, we compared the differentiation of pancreatic endocrine cells between Insm1 null and Insm1 SNAG domain mutants (Insm1delSNAG) to explore the specific function of the SNAG domain of Insm1. We show that the delta-cell number is increased in Insm1delSNAG but not in Insm1 null mutants as compared to the control mice. We also show a less severe reduction of the beta-cell number in Insm1delSNAG as that in Insm1 null mutants. In addition, similar deficits are observed in alpha-, PP- and epsilon-cell in Insm1delSNAG and Insm1 null mutants. We further identified that the increased delta-cell number is due to beta- to delta-cell transdifferentiation. Mechanistically, the SNAG domain of Insm1 interacts with Lsd1, the demethylase of H3K4me1/2. Mutation in the SNAG domain of Insm1 results in impaired recruitment of Lsd1 and increased H3K4me1/2 levels at Hhex loci that are bound by Insm1, thereby promoting the transcriptional activity of the delta-cell-specific gene Hhex. Our study has identified a novel function of the SNAG domain of Insm1 in the regulation of pancreatic endocrine cells differentiation, particularly in the repression of beta- to delta-cell transdifferentiation.

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The SNAG Domain of Insm1 Regulates Pancreatic Endocrine Cell Differentiation and Represses Beta- to Delta-Cell Transdifferentiation

Diabetes ◽

10.2337/db20-0883 ◽

2021 ◽

pp. db200883

Author(s):

Xuehua Liang ◽

Hualin Duan ◽

Yahui Mao ◽

Ulrich Koestner ◽

Yiqiu Wei ◽

...

Keyword(s):

Cell Differentiation ◽

Endocrine Cell ◽

Pancreatic Endocrine Cell ◽

Cell Transdifferentiation ◽

Delta Cell

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The distribution of endocrine cell progenitors in the gut of chick embryos

Development ◽

10.1242/dev.82.1.131 ◽

1984 ◽

Vol 82 (1) ◽

pp. 131-145

Author(s):

B. B. Rawdon ◽

Beverley Kramer ◽

Ann Andrew

Keyword(s):

Gastrointestinal Tract ◽

Progenitor Cells ◽

Digestive Tract ◽

Pancreatic Polypeptide ◽

Endocrine Cell ◽

Endocrine Cells ◽

Chick Embryos ◽

Intact Embryo ◽

Pancreatic Endocrine Cells ◽

Gut Endocrine Cells

The aim of this experiment was to find out whether or not, at early stages of development, progenitors of the various types of gut endocrine cells are localized to one or more specific regions of the gastrointestinal tract. Transverse strips of blastoderm two to four somites in length were excised between the levels of somites 5 and 27 in chick embryos at 5- to 24-somite stages and were cultured as chorioallantoic grafts. The distribution of endocrine cells in the grafts revealed confined localization of progenitor cells only in the case of insulinimmunoreactive cells. Theprogenitors of cells with somatostatin-, pancreatic polypeptide-, glucagon-, secretin-, gastrin/CCK-, motilin-, neurotensin- and serotonin-like immunoreactivity were distributed along the length of the presumptive gut at the time of explantation; indeed, in many cases they were more widespread than are their differentiated progeny in normal gut of the same age. This finding indicates that conditions in grafts must differ from those that operate in the intact embryo. Also it may explain the occurrence of ectopic gut or pancreatic endocrine cells in tumours of the digestive tract.

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Transcription Factor Hepatocyte Nuclear Factor 6 Regulates Pancreatic Endocrine Cell Differentiation and Controls Expression of the Proendocrine Gene ngn3

Molecular and Cellular Biology ◽

10.1128/mcb.20.12.4445-4454.2000 ◽

2000 ◽

Vol 20 (12) ◽

pp. 4445-4454 ◽

Cited By ~ 238

Author(s):

Patrick Jacquemin ◽

Serge M. Durviaux ◽

Jan Jensen ◽

Catherine Godfraind ◽

Gerard Gradwohl ◽

...

Keyword(s):

Transcription Factor ◽

Cell Differentiation ◽

Endocrine Cell ◽

Endocrine Cells ◽

Glucose Transporter ◽

Nuclear Factor ◽

Hepatocyte Nuclear Factor ◽

Mouse Development ◽

Endocrine Differentiation ◽

Glucose Transporter 2

ABSTRACT Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. We have investigated the role of HNF-6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6 −/− embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin 3 (Ngn-3), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their β cells were deficient in glucose transporter 2 expression. Adult hnf6 −/− mice were diabetic. Taken together, our data demonstrate that HNF-6 controls pancreatic endocrine differentiation at the precursor stage and identify HNF-6 as the first positive regulator of the proendocrine gene ngn3in the pancreas. They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans.

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Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation

Journal of Biological Chemistry ◽

10.1074/jbc.m610986200 ◽

2007 ◽

Vol 282 (20) ◽

pp. 15228-15237 ◽

Cited By ~ 50

Author(s):

Ghislaine Guillemain ◽

Gaëlle Filhoulaud ◽

Gabriela Da Silva-Xavier ◽

Guy A. Rutter ◽

Raphaël Scharfmann

Keyword(s):

Cell Differentiation ◽

Endocrine Cell ◽

Pancreatic Endocrine Cell

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The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

Journal of Biological Chemistry ◽

10.1074/jbc.m110.108019 ◽

2010 ◽

Vol 285 (18) ◽

pp. 13863-13873 ◽

Cited By ~ 14

Author(s):

Vincianne Verbruggen ◽

Olivier Ek ◽

Daphné Georlette ◽

François Delporte ◽

Virginie Von Berg ◽

...

Keyword(s):

Cell Differentiation ◽

Endocrine Cell ◽

Pancreatic Endocrine Cell

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Dapagliflozin promotes beta cell regeneration by inducing pancreatic endocrine cell phenotype conversion in type 2 diabetic mice

Metabolism ◽

10.1016/j.metabol.2020.154324 ◽

2020 ◽

Vol 111 ◽

pp. 154324

Author(s):

Rui Wei ◽

Xiaona Cui ◽

Jin Feng ◽

Liangbiao Gu ◽

Shan Lang ◽

...

Keyword(s):

Beta Cell ◽

Endocrine Cell ◽

Cell Phenotype ◽

Cell Regeneration ◽

Diabetic Mice ◽

Beta Cell Regeneration ◽

Pancreatic Endocrine Cell ◽

Type 2 Diabetic

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MesenchymalHox6function is required for mouse pancreatic endocrine cell differentiation

Development ◽

10.1242/dev.126888 ◽

2015 ◽

Vol 142 (22) ◽

pp. 3859-3868 ◽

Cited By ~ 23

Author(s):

Brian M. Larsen ◽

Steven M. Hrycaj ◽

Micaleah Newman ◽

Ye Li ◽

Deneen M. Wellik

Keyword(s):

Cell Differentiation ◽

Endocrine Cell ◽

Pancreatic Endocrine Cell

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Heterogeneity of chromogranin A-derived peptides in bovine gut, pancreas and adrenal medulla

Biochemical Journal ◽

10.1042/bj2760471 ◽

1991 ◽

Vol 276 (2) ◽

pp. 471-479 ◽

Cited By ~ 48

Author(s):

A Watkinson ◽

A C Jönsson ◽

M Davison ◽

J Young ◽

C M Lee ◽

...

Keyword(s):

Endocrine Cell ◽

Cell Biology ◽

Chromogranin A ◽

Endocrine Cells ◽

Cell Types ◽

Intact Protein ◽

Pancreatic Endocrine Cells ◽

Gastric Corpus ◽

Adrenal Chromaffin ◽

Bovine Pancreas

Chromogranin A is produced in many endocrine cell types, and is widely used as a marker in endocrine-cell pathology and secretory-cell biology. There is some evidence that it may be proteolytically processed to yield the putative pancreatic regulatory peptide, pancreastatin, and, in order to characterize the relevant pathways in gastrointestinal and pancreatic endocrine cells, we have used, in radioimmunoassay, site-directed antibodies to pancreastatin itself (L331) and to a sequence of chromogranin A immediately C-terminal to pancreastatin (L300). The latter antibody revealed three major forms of immunoreactivity of 8 kDa and five peptides of approx. 3 kDa in bovine pancreas and gut extracts. The 8 kDa peptides were characterized as chromogranin A-(248-313)-peptides, i.e. C-terminally extended forms of pancreastatin; two of the 8 kDa variants differed in two positions, confirming a polymorphism predicted from cDNA sequencing. One of the 3 kDa peptides was characterized as chromogranin A-(297-313)-peptide, i.e. the C-terminal heptadecapeptide of the 8 kDa peptide that would be liberated after cleavage to yield pancreastatin. On the basis of chromatographic studies, immunohistochemistry and the stoichiometry of different immunoreactive peptides, three different pathways of chromogranin A processing were identified: in adrenal chromaffin cells chromogranin A existed mainly as the unmodified intact protein, in pancreatic islet and gastric antral endocrine cells pancreastatin and the 3 kDa peptides were major products, but in small intestine and gastric corpus endocrine cells there was little nor no pancreastatin and the 8 kDa cleavage product predominated. There are therefore important differences in the distribution of chromogranin A-derived peptides between quite closely related populations of endocrine cells that are attributable not only to variable post-translational cleavage but also to the expression of different primary sequences. It seems possible that in different cell types chromogranin A-derived peptides might subserve a variety of different functions.

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