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
AUTHORS (5)
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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