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

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
DOI: 10.1016/j.molmet.2021.101267 Publication Date: 2021-06-08T07:36:31Z
ABSTRACT
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.
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