Couceiro, J. | Search bioRxiv

bioRxiv2026

A whole-genome screen identifies a bilateral Flower-Grindelwald/TNFR-Veli/LIN-7 communication module in cell competition

Viable yet suboptimal ("loser") cells can be recognized and selectively eliminated when in the presence of neighboring fitter ("winner") cells through cell competition, thereby promoting optimal tissue fitness and homeostasis. One mechanism through which cells compare their relative fitness levels relies on isoforms of the conserved transmembrane protein Flower (Fwe). Despite the role of Fwe-dependent cell selection in several pathophysiological processes, little is known about downstream components of this pathway. In this study, we develop a versatile clonal interaction assay in Drosophila, the Easy Win Assay. By overexpressing human FWE1 Lose isoform to trigger cell competition, we perform an unbiased whole-genome RNAi screen and identify new pathway modulators. We show that the receptor Grindelwald/TNFR is necessary in either winner or loser cells to drive Eiger/TNF--independent elimination of losers, whereas the scaffolding protein Veli/LIN-7 is simultaneously required in both cell populations. We further demonstrate that Fwe, Grindelwald and Veli redistribute to establish a previously undescribed bilateral communication module at winner-loser interfaces, promoting intercellular communication and elimination of loser cells. These findings show that distinct cell elimination pathways converge on a common execution module while remaining independently regulated upstream, enabling flexible recognition and elimination of diverse damaged or dangerous cells.

cell biology↗

bioRxiv2025

Dietary Interventions Modulate Cell Competition and Locomotor Decline in an Alzheimer's Disease Drosophila Model

Alzheimers Disease (AD) is a neurodegenerative disorder characterised by the accumulation of Amyloid-beta 42 (A{beta}42) plaques and cognitive decline. Using Drosophila models, we investigated the impact of diet on cell competition, a process that eliminates unfit cells and is involved in AD progression. Cell competition is present in AD flies, where unfit neurons express fweLoseB and azot, leading to their elimination and motor improvements. In this study, we fed AD and control (healthy) flies with either a yeast-based diet (YBD) or a synthetic diet (SAA) for up to 28 days and evaluated cell competition at the cellular level and locomotion as behavioural output. AD flies fed with YBD exhibited a peak of cell competition at day 14 of feeding, being cyclical over time and followed by a progressive locomotion decline. In contrast, the SAA diet delayed the activation of cell competition until day 21, coinciding with locomotion restoration. Moreover, the synthetic diet postponed A{beta} formation, suggesting a slower progression of AD. Overexpression of the human Flower (hFWE) isoforms in Drosophila photoreceptors revealed their conserved function in regulating cell competition, with hFWE1 identified as the sole loser isoform in neuronal context. Conversely, hFWE2, a winner isoform, induced higher levels of cell competition in a diet-dependent manner. hFWE3 and hFWE4 induced a milder effect on cell competition but also have a winner-like function. In YBD-fed AD flies, hFWE2 failed to promote efficient elimination of unfit cells over time, as these flies exhibited even worse locomotion decline than control flies without hFWE2. In contrast with SAA, expression of hFWE2 induced better locomotion outcomes. Our data seems to indicate that diet may regulate AD progression through cell competition regulation, highlighting the complex interplay between diet, cell competition, and AD progression and providing insights into potential therapeutic strategies.

cell biology↗