Hepatocyte maturation is arrested in mouse liver lacking the splicing factor SRSF3 (SRp20)

Abstract

SRSF3 is the smallest member of the highly conserved SR protein family that has numerous roles in mRNA metabolism, from transcription to translation. To investigate the role of SRSF3 in postnatal hepatic function, we used Cre‐loxP‐mediated gene technology to delete SRSF3 specifically in hepatocytes in mice. Deletion of SRSF3 inhibits hepatocyte maturation as livers from mice lacking SRSF3 exhibit a fetal phenotype characterized by increased expression of the fetal isozyme of pyruvate kinase (M‐PK), persistent expression of alpha‐fetoprotein and H19 mRNA. The livers also show increased expression of the fetal isoform of the insulin receptor (IR‐A). The expression of several genes that regulate glucose and lipid metabolism in the mature liver is significantly reduced in SRSF3−/− liver, and glycogen levels are decreased. Global gene expression and exon microarray analyses identified multiple splicing and expression changes in the SRSF3−/− liver. Interestingly, some of these changes alter expression of major hepatic transcription factors that play crucial role in development and metabolism. Thus, SRSF3 directs a genetic program required for morphological and functional differentiation of hepatocytes and the hepatocyte SRSF3 knock‐out mice provide a new model to study metabolic dysregulation and liver disease.This work has been supported by VA Merit Grant Award.