REST represses a subset of the pancreatic endocrine differentiation program.

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State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_1BD305A63293
Type
Article: article from journal or magazin.
Collection
Publications
Title
REST represses a subset of the pancreatic endocrine differentiation program.
Journal
Developmental Biology
Author(s)
Martin D., Kim Y.H., Sever D., Mao C.A., Haefliger J.A., Grapin-Botton A.
ISSN
1095-564X (Electronic)
ISSN-L
0012-1606
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
405
Number
2
Pages
316-327
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
To contribute to devise successful beta-cell differentiation strategies for the cure of Type 1 diabetes we sought to uncover barriers that restrict endocrine fate acquisition by studying the role of the transcriptional repressor REST in the developing pancreas. Rest expression is prevented in neurons and in endocrine cells, which is necessary for their normal function. During development, REST represses a subset of genes in the neuronal differentiation program and Rest is down-regulated as neurons differentiate. Here, we investigate the role of REST in the differentiation of pancreatic endocrine cells, which are molecularly close to neurons. We show that Rest is widely expressed in pancreas progenitors and that it is down-regulated in differentiated endocrine cells. Sustained expression of REST in Pdx1(+) progenitors impairs the differentiation of endocrine-committed Neurog3(+) progenitors, decreases beta and alpha cell mass by E18.5, and triggers diabetes in adulthood. Conditional inactivation of Rest in Pdx1(+) progenitors is not sufficient to trigger endocrine differentiation but up-regulates a subset of differentiation genes. Our results show that the transcriptional repressor REST is active in pancreas progenitors where it gates the activation of part of the beta cell differentiation program.
Keywords
Animals, Blood Glucose/metabolism, Cell Differentiation, Down-Regulation, Endocrine Cells/cytology, Endocrine Cells/metabolism, Endocrine System/metabolism, Gene Deletion, Gene Expression Regulation, Developmental, Homeodomain Proteins/metabolism, Islets of Langerhans/metabolism, Mice, Mice, Knockout, Neurons/metabolism, Pancreas/embryology, Pancreas/metabolism, Repressor Proteins/physiology, Stem Cells/cytology, Trans-Activators/metabolism, Transgenes
Pubmed
Web of science
Open Access
Yes
Create date
26/10/2016 15:31
Last modification date
20/08/2019 13:52
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