Genetic landscaping of cell competition uncovers two core pathways mediated by Xrp1 or Eiger/TNF in Drosophila

Abstract

Genetic studies in Drosophila have uncovered diverse molecules that drive cell competition, a quality control mechanism whereby less-fit cells are eliminated through interactions with fitter neighboring cells. This has raised the fundamental question of whether cell competition converges on shared molecular pathways, despite being initiated by distinct genetic alterations. To address this, we conducted a large-scale genetic screen in Drosophila across ∼12,500 mutant chromosomes and isolated 63 mutations that convert cells into losers of cell competition. Subsequent genetic analyses revealed that the vast majority of these "loser" mutations induce cell competition through one of two mechanisms: the bZip transcription factor Xrp1 or the Eiger/TNF-JNK signaling pathway. Genomic analyses further identified sets of genes required for nucleocytoplasmic mRNA export and septate junction function, but not cell polarity, as responsible genes for Xrp1- and Eiger/TNF-mediated cell competition, respectively. Our findings support the view that cell competition acts as a surveillance system that detects specific cellular malfunctions and eliminates defective cells via one of two core pathways mediated by Xrp1 or Eiger/TNF.

Keywords: Dros2026; JNK; TNF; Xrp1; cell competition.