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Genetic landscaping of cell competition uncovers two core pathways mediated by Xrp1 or Eiger/TNF in Drosophila
Ryo Matsumoto1, Hiroshi Kanda1, Aya Kawasaki1
1Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoecho, Sakyo-ku, Kyoto 606-8501, Japan.
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.
Insights
Cell competition eliminates unfit cells via two main pathways: the Xrp1 transcription factor or the Eiger/TNF-JNK signaling pathway. This quality-control mechanism identifies and removes defective cells in Drosophila.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- Cell competition is a crucial quality-control process where less-fit cells are eliminated by fitter neighbors.
- Distinct genetic alterations can initiate cell competition, raising questions about shared molecular pathways.
Purpose of the Study:
- To investigate whether cell competition converges on shared molecular pathways despite diverse genetic triggers.
- To identify the core molecular mechanisms underlying cell competition in Drosophila.
Main Methods:
- Conducted a large-scale genetic screen of approximately 12,500 mutant Drosophila chromosomes.
- Isolated and analyzed 63 mutations causing cells to become 'losers' in cell competition.
- Performed genomic analyses to identify responsible genes for specific cell competition pathways.
Main Results:
- The majority of 'loser' mutations induced cell competition via either the bZip transcription factor Xrp1 or the Eiger/TNF-JNK signaling pathway.
- Identified genes involved in nucleocytoplasmic mRNA export as crucial for Xrp1-mediated competition.
- Identified genes involved in septate junction function as crucial for Eiger/TNF-mediated competition.
Conclusions:
- Cell competition acts as a surveillance system detecting cellular malfunctions.
- Two core pathways, mediated by Xrp1 or Eiger/TNF, are responsible for eliminating defective cells.
- Findings elucidate conserved molecular mechanisms underlying cell competition and tissue homeostasis.
