Miret, M. | bioRxiv Science

bioRxiv2022

Control of pancreatic islet function and glucose homeostasis by a novel microexon program misregulated in type 2 diabetes

Pancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and their abnormal function causes diabetes or hypoglycemia. Here, we uncover a conserved program of alternative microexons included in mRNAs of islet cells, particularly in genes involved in vesicle transport and exocytosis. Islet microexons (IsletMICs) are regulated by the RNA binding protein SRRM3 and represent a subset of the larger neural program that are particularly sensitive to the levels of this regulator. Both SRRM3 and IsletMICs are induced by elevated glucose levels, and depletion of SRRM3 in beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently, SRRM3 mutant mice display defects in islet cell identity and function, leading to hyperinsulinemic hypoglycemia. Importantly, human genetic variants that influence SRRM3 expression and IsletMIC inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk.

molecular biology↗

bioRxiv2021

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians

The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as a novel player in this dispute. Mbnl3 belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of RNA metabolism in association with cellular differentiation. We find that, in eutherians, Mbnl3 has become specifically expressed in placenta and has undergone accelerated sequence evolution leading to changes in its RNA binding specificities. Although its molecular roles are partly redundant with those of Mbnl2, Mbnl3 has also acquired novel biological functions. In particular, whereas Mbnl2;Mbnl3 double knockout mice display severe placental maturation defects leading to strong histological and functional abnormalities, Mbnl3 knockout alone results in increased placental growth and favors placental and fetal resource allocation during limiting conditions.

evolutionary biology↗