Heterozygous disruption of Snrpf causes post-implantation embryonic lethality with RNA splicing perturbation in mice.

Abstract

RNA splicing is a post-transcriptional modification process of precursor mRNA. This process is regulated by the macromolecular complex known as the spliceosome. One of the major components of spliceosomes is the small nuclear ribonucleoprotein (snRNP). Snrpf encodes SmF, a core protein component of the snRNP. Although SNRPF has been implicated in human disease, its function in vivo remains poorly understood. In this study, we showed that homozygous mutation of Snrpf caused peri-implantation lethality, while heterozygous Snrpf mutant mice exhibited embryonic lethality between implantation and placentation with variable expressivity. The heterozygous mutants exhibited abnormal morphology, delayed formation of the three germ layers, and increased apoptosis. Transcriptome analysis revealed heterozygous mutation of Snrpf altered gene expression, increased intron retention, and caused both exon skipping and exon inclusion. We further found that a subset of exons with shorter lengths and shorter flanking introns was more sensitive to exon inclusion in Snrpf heterozygous mutants. These findings suggested that Snrpf is essential for early embryonic development and required for proper RNA splicing and gene expression. This study provides new insights for future studies of RNA splicing in vivo.