The miR-200–Zeb1 axis regulates key aspects of β-cell function and survival in vivo

• DOI: 10.1016/j.molmet.2021.101267
• Publication Date: 2021-06-08T07:36:31Z
• Authors: Alexandra C. Title; Pamuditha N. Silva; Svenja Godbersen; Lynn Hasenöhrl; Markus Stoffel
• Keywords: Mice, Knockout; 0301 basic medicine; 0303 health sciences; microRNA; Zinc Finger E-box-Binding Homeobox 1; Apoptosis; Endoplasmic Reticulum Stress; RC31-1245; Double-negative feedback loop; β-cell dedifferentiation; Epithelial-to-mesenchymal transition; Double-negative feedback loop; Islet aggregation; ER stress; microRNA; Mice; MicroRNAs; 03 medical and health sciences; Epithelial-to-mesenchymal transition; Insulin-Secreting Cells; β-cell dedifferentiation; Insulin Secretion; Animals; Original Article; Islet aggregation; ER stress; Internal medicine; Cells, Cultured

The miR-200–Zeb1 axis regulates the epithelial-to-mesenchymal transition (EMT), differentiation, and resistance to apoptosis. A better understanding of these processes in diabetes is highly relevant, as β-cell dedifferentiation apoptosis contribute loss functional mass progression. Furthermore, EMT promotes identity vitro expansion human islets. Though miR-200 family has previously been identified a regulator vivo, studies focusing on Zeb1 are lacking. aim this study was thus investigate role function survival vivo. involved double-negative feedback loop. We characterized mouse model which binding sites 3′UTR mutated (Zeb1200), leading physiologically relevant upregulation mRNA expression. investigated via metabolic tests analysis isolated Further insights into distinct contributions branches loop were obtained by crossing Zeb1200 allele background miR-141–200c overexpression. Mild derepression vivo led broad transcriptional changes islets affecting identity, EMT, insulin secretion, cell–cell junctions, unfolded protein response (UPR), ER stress. aggregation secretion dissociated mice homozygous for mutation (Zeb1200M) impaired, Zeb1200M resistant thapsigargin-induced stress ex had increased circulating proinsulin levels but no overt phenotype, reflecting strong compensatory ability maintain glucose homeostasis. This signifies importance regulating key aspects survival. developing therapeutic strategies inducing redifferentiation maintaining islet expansion.