REST represses a subset of the pancreatic endocrine differentiation program

Autor: Yung Hae Kim, Jacques-Antoine Haefliger, Chai An Mao, Anne Grapin-Botton, David Martin, Dror Sever
Rok vydání: 2015
Předmět:
Blood Glucose
medicine.medical_specialty
Cellular differentiation
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
Enteroendocrine cell
Endocrine System
Biology
Alpha cell
Article
Islets of Langerhans
Internal medicine
NRSF
medicine
Pancreas
Molecular Biology
Rest (music)
Homeodomain Proteins
Neurons
Stem Cells
Diabetes
Beta cells
Cell Biology
Cell biology
Repressor Proteins
medicine.anatomical_structure
Endocrinology
Repressor
Trans-Activators
PDX1
Beta cell
Stem cell
Islets
Endocrine Cells
Developmental Biology
Zdroj: Developmental Biology, vol. 405, no. 2, pp. 316-327
Developmental biology
ISSN: 0012-1606
DOI: 10.1016/j.ydbio.2015.07.002
Popis: 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. (C) 2015 Elsevier Inc. All rights reserved.
Databáze: OpenAIRE
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