REST represses a subset of the pancreatic endocrine differentiation program

TY - JOUR

T1 - REST represses a subset of the pancreatic endocrine differentiation program

AU - Martin, David

AU - Kim, Yung-Hae

AU - Sever, Dror

AU - Mao, Chai-An

AU - Haefliger, Jacques-Antoine

AU - Grapin-Botton, Anne

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Glucose

KW - Cell Differentiation

KW - Down-Regulation

KW - Endocrine Cells

KW - Endocrine System

KW - Gene Deletion

KW - Gene Expression Regulation, Developmental

KW - Homeodomain Proteins

KW - Islets of Langerhans

KW - Mice

KW - Mice, Knockout

KW - Neurons

KW - Pancreas

KW - Repressor Proteins

KW - Stem Cells

KW - Trans-Activators

KW - Transgenes

U2 - 10.1016/j.ydbio.2015.07.002

DO - 10.1016/j.ydbio.2015.07.002

M3 - Journal article

C2 - 26156633

SN - 0012-1606

VL - 405

SP - 316

EP - 327

JO - Developmental Biology

JF - Developmental Biology

IS - 2

ER -