Delayed aneuploidy stress response of neural stem cells impairs adult lifespan in flies

Summary Studying aneuploidy during organism development has strong limitations, as chronic mitotic perturbations used to generate aneuploidy result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their lifespan. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, complex array of karyotypes and cellular abnormalities. Notably, when other brain cell-lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed, indicating that stemness state confers resistance to aneuploidy. Sparing solely the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult lifespan, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy. Highlights Reversible depletion of cohesin results in just a round or two of aberrant cell divisions, generating high levels of aneuploidy. Larvae challenged with aneuploidy during development hatch into impaired adults. Few cell cycles are sufficient for chromosomal instability to emerge from a previously stable aneuploid state. Neural stemness delays aneuploidy stress response. Protecting only the neural tissue from aneuploidy rescues adult abnormalities and lifespan.