Abstract
The mRNA export pathway is responsible for the transport of mRNAs from the nucleus to the cytoplasm, and thus is essential for protein production and normal cellular functions. A partial loss of function allele of the mRNA export factor Nxt1 in Drosophila shows reduced viability and sterility. A previous study has shown that the male fertility defect is due to a defect in transcription and RNA stability, indicating the potential for this pathway to be implicated in processes beyond the known mRNA transport function. Here we investigate the reduced viability of Nxt1 partial loss of function mutants, and describe a defect in growth and maintenance of the larval muscles, leading to muscle degeneration. RNA-seq revealed reduced expression of a set of mRNAs, particularly from genes with long introns in Nxt1 mutant carcass. We detected differential expression of circRNA, and significantly fewer distinct circRNAs expressed in the mutants. Despite the widespread defects in gene expression, muscle degeneration was rescued by increased expression of the costamere component tn (abba) in muscles. This is the first report of a role for the RNA export pathway gene Nxt1 in the maintenance of muscle integrity. Our data also links the mRNA export pathway to a specific role in the expression of mRNA and circRNA from common precursor genes, in vivo.
Highlights
Regulation of mRNA expression depends on transcriptional regulatory processes, such as transcription factor and repressor binding to DNA
The recognition of mRNAs as nuclear export cargoes by the nuclear pores depends on the binding of the Nxf1/Nxt1 protein heterodimer, which directly interacts with nuclear pore components
We found a striking overlap: 85% (466 of the 567) genes 4x or more down-regulated in Nxt1 muscles had at least one read consistent with a circRNA. 199 of these genes were in the higher confidence set associated with at least 10 circRNA reads. 57 of the 186 genes that were at least 8Â down-regulated in Nxt1 muscles were in the high confidence circRNA set
Summary
Regulation of mRNA expression depends on transcriptional regulatory processes, such as transcription factor and repressor binding to DNA. Recruitment of the spliceosome, and subsequent completion of splicing of each intron, results in deposition of the exon junction complex (EJC) at the splice site (Le Hir et al 2000). This facilitates TREX recruitment (Le Hir et al 2001), TREX recruitment occurs independently of splicing, mediated both by cap-dependent interactions, and interactions between ALYREF and the body of transcripts (Cheng et al 2006; Chi et al 2013; Viphakone et al 2019). ALYREF acts to stimulate the RNA-binding activity of Nxf, and ensures that the Nxf1/Nxt heterodimer is recruited to the mRNA, permitting its subsequent export. Recruitment of export factors occurs cotranscriptionally, and is typically completed before the final act of mRNA production, namely cleavage and polyadenlyation
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