Loss of function of the RNA export factor, Nxt1, in Drosophila causes muscle degeneration and reduced expression of genes with long introns.

Abstract

The RNA export pathway is essential for export-competent mRNAs to pass from the nucleus into the cytoplasm, and thus is essential for protein production and normal function of cells. Drosophila with partial loss of function of Nxt1, a core factor in the pathway, show reduced viability and male and female sterility. The male sterility has previously been shown to be caused by defects in testis-specific gene expression, particularly of genes without introns. Here we describe a specific defect in growth and maintenance of the larval muscles, leading to muscle degeneration in Nxt1 mutants. RNAseq revealed reduced expression of mRNAs of many genes in Nxt1 mutant muscles. Despite this, the degeneration was rescued by increased expression of a single gene, the costamere component tn (abba), in muscles. Genes under-expressed in the mutant typically have long introns, and most normally encode circular RNAs in addition to mRNAs. This is the first report of a specific role for the RNA export pathway gene Nxt1 in muscle integrity. Our data on Nxt1 links the mRNA export pathway to a global role in mRNA expression of genes that also produce circular RNAs, in vivo. Author summaryIn eukaryotic cells the DNA encoding instructions for protein synthesis is located in the nucleus, it is transcribed to generate pre-mRNA, which is processed at both ends and spliced to remove internal spacer regions (introns) to generate mRNA. This mRNA is then transported by the mRNA export pathway via nuclear pores to the cytoplasm for protein synthesis. We have previously shown that reduction in activity of a specific protein in the mRNA export pathway, Nxt1, has an additional role in testis-specific transcription. Here we describe a further role for this protein specifically in gene expression, particularly of genes with long introns, and in muscle maintenance. Drosophila larvae with reduced Nxt1 activity have normal muscle pattern when they are small, but show muscular atrophy and degeneration as they grow, resulting in significant defects in their movement speed. We discovered that expression of many genes is reduced in the mutant larvae, but that restoring the expression of just one of these, abba, the Drosophila homologue of Trim32 (a human gene involved in muscular dystrophy) is capable of preventing the muscle degeneration.