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. The proteomic complexity of mammalian genomes is greatly expanded by the selective use of exons via alternative splicing. The spatiotemporal expression of alternatively spliced mRNA isoforms contributes substantially to cell differentiation and fate specification and hence influences organogenesis. Reprogramming of alternative splicing during cell differentiation can be achieved by induction of a tissue-specific splicing regulator or by switched expression of one factor to another one that has different or even antagonistic splicing activities. Alternative splicing also provides a mechanism for responding to metabolic prompts (1, 2). Gaining comprehensive insight into alternative splicing remains an imperative goal in the postgenome era.The RNA-binding motif 4 (RBM4) protein has multiple functions in mRNA metabolism; it primarily modulates alterative splicing of precursor mRNAs and regulates mRNA translation (3). We previously reported that RBM4 represses expression of the splicing factor polypyrimidine tract-binding protein (PTB) via alternative splicing-coupled nonsense-mediated mRNA decay during muscle cell differentiation (4). Moreover, RBM4 also modulates the use of alternative exons of many mRNAs encoding muscle differentiation factors or cytoskeletal proteins. Therefore, we deduced that RBM4 promotes myogenesis through its role in altering the repertoire of mRNA isoforms. To further our understanding of the physiological function of RBM4, we attempted to exploit the gene knockout strategy in mice. Previous splicing factor knockout and transgenic studies have revealed the functional consequences of alternative splicing in mammalian development and physiological processes (5). For example, cardiac tissue-specific disruption of the splicing factor gene Srsf1 resulted in abnormal cardiac phenotypes in mice and, moreover, revealed a group of ...

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