RBM4 Promotes Pancreas Cell Differentiation and Insulin Expression

Abstract

The RNA-binding protein RNA-binding motif protein 4 (RBM4) modulates alternative splicing of muscle-specific mRNA isoforms during muscle cell differentiation. To better understand the physiological function of RBM4, we exploited a gene knockout strategy in the present study. Mice with targeted disruption of one of the two Rbm4 genes exhibited hyperglycemia coincident with reduced levels of serum insulin and reduced size of pancreatic islets. The embryonic pancreases of Rbm4-deficient mice showed reduced expression or aberrant splicing of many transcripts encoding factors required for pancreas cell differentiation and function. Using pancreatic acinar AR42J cells, we demonstrated that RBM4 promoted insulin gene expression by altering the isoform balance of the transcription factors Isl1 and Pax4 via alternative splicing control. RBM4 overexpression was sufficient to convert AR42J cells into insulin-producing cells. Moreover, RBM4 may mediate glucose-induced insulin expression and insulin receptor isoform switches. These results suggest that RBM4 may have role in promoting pancreas cell differentiation and endocrine function, essentially via alternative splicing regulation.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01266-12.

ACKNOWLEDGMENTS

We greatly appreciate the technical services provided by the Transgenic Mouse Model Core Facility of the National Core Facility Program for Biotechnology, National Science Council, and the Gene Knockout Mouse Core Laboratory of the National Taiwan University Center of Genomic Medicine. We are very grateful to C.-N. Shen for his generous provision of materials and technical suggestions and critical reading of the manuscript.

This work was supported by National Science Council grant NSC 100-2311-B-001-011-MY3.

We declare no conflicts of interest.