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

ABSTRACT: Pancreatic ?-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in ?-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 ? cell maturation and identity. Mice with ? cell-specific Cnot3 deletion (Cnot3?KO) exhibit impaired glucose tolerance, decreased ? cell mass, and they gradually develop diabetes. Cnot3?KO islets display decreased expression of key regulators of ? cell maturation and function. Moreover, they show an increase of progenitor cell markers, ? cell-disallowed genes, and genes relevant to altered ? cell function. Cnot3?KO 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 ? cell identity.

SUBMITTER: Mostafa D 

PROVIDER: S-EPMC7455721 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature