Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

• DOI: 10.1038/s42003-020-01201-y
• Publication Date: 2020-08-28T10:09:48Z
• Authors: Dina Mostafa; Akiko Yanagiya; Eleni Georgiadou; Yibo Wu; Theodoros Stylian...; Guy A. Rutter; Toru Suzuki; Tadashi Yamamoto
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Proteome; Cell Count; Cell Differentiation; Glucose Tolerance Test; Lipids; Models, Biological; Article; Diabetes Mellitus, Experimental; Disease Models, Animal; 03 medical and health sciences; Glucose; Phenotype; Insulin-Secreting Cells; Insulin Secretion; Animals; Insulin; Obesity; RNA, Messenger; Transcriptome; Transcription Factors

AbstractPancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4–NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.