Notch-mediated Ephrin signaling disrupts islet architecture and β cell function Journal Article
| Authors: | Bartolomé, A.; Suda, N.; Yu, J.; Zhu, C.; Son, J.; Ding, H.; Califano, A.; Accili, D.; Pajvani, U. B. |
| Article Title: | Notch-mediated Ephrin signaling disrupts islet architecture and β cell function |
| Abstract: | Altered islet architecture is associated with β cell dysfunction and type 2 diabetes (T2D) progression, but molecular effectors of islet spatial organization remain mostly unknown. Although Notch signaling is known to regulate pancreatic development, we observed "reactivated"β cell Notch activity in obese mouse models. To test the repercussions and reversibility of Notch effects, we generated doxycycline-dependent, β cell-specific Notch gain-of-function mice. As predicted, we found that Notch activation in postnatal β cells impaired glucose-stimulated insulin secretion and glucose intolerance, but we observed a surprising remnant glucose intolerance after doxycycline withdrawal and cessation of Notch activity, associated with a marked disruption of normal islet architecture. Transcriptomic screening of Notch-active islets revealed increased Ephrin signaling. Commensurately, exposure to Ephrin ligands increased β cell repulsion and impaired murine and human pseudoislet formation. Consistent with our mouse data, Notch and Ephrin signaling were increased in metabolically inflexible β cells in patients with T2D. These studies suggest that β cell Notch/Ephrin signaling can permanently alter islet architecture during a morphogenetic window in early life. © 2022, Bartolomé et al. |
| Keywords: | signal transduction; controlled study; human cell; nonhuman; protein function; animal cell; mouse; animal tissue; cell function; cell structure; gene expression; cell maturation; animal experiment; animal model; genotype; obesity; notch receptor; morphogenesis; insulin; glucose blood level; cell aggregation; glucose; insulin blood level; doxycycline; pancreas islet beta cell; cell activation; cell adhesion; non insulin dependent diabetes mellitus; glucose tolerance test; drug exposure; ephrin; transcriptome sequencing; cytoarchitecture; notch signaling; ephrin a5; glucose intolerance; gain of function mutation; human; male; female; article; insulin release; ephrin signaling; glucose stimulated insulin secretion |
| Journal Title: | JCI Insight |
| Volume: | 7 |
| Issue: | 6 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2022-03-22 |
| Start Page: | e157694 |
| Language: | English |
| DOI: | 10.1172/jci.insight.157694 |
| PUBMED: | 35167496 |
| PROVIDER: | scopus |
| PMCID: | PMC8986078 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
