serval:BIB_1BD305A63293
REST represses a subset of the pancreatic endocrine differentiation program.
10.1016/j.ydbio.2015.07.002
000360255800013
26156633
Martin
D.
author
Kim
Y.H.
author
Sever
D.
author
Mao
C.A.
author
Haefliger
J.A.
author
Grapin-Botton
A.
author
article
2015
Developmental Biology
1095-564X
0012-1606
journal
405
2
316-327
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
University of Lausanne
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