DlL1- And Dll4-mediated Notch signaling is essential for adult pancreatic islet homeostasis

Marina Rubey, Nirav Florian Chhabra, Daniel Gradinger, Adrián Sanz-Moreno, Heiko Lickert, Gerhard K.H. Przemeck, Martin Hrab de Angelis

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion.

Original languageEnglish
Pages (from-to)915-926
Number of pages12
JournalDiabetes
Volume69
Issue number5
DOIs
StatePublished - 1 May 2020

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