Induced aneuploidy in neural stem cells triggers a delayed stress response and impairs adult life span in flies

Abstract

Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually 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 life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a 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. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.

Abstract

A novel genetic tool for inducing chromosomal imbalance in fruit flies in an acute and time-controlled manner reveals that the brain is the most sensitive tissue when it comes to coping with abnormal karyotypes during development.

Author summary

Aneuploidy—the presence of an abnormal number of chromosomes in a cell—is a hallmark of cancer and developmental disorders. However, it is notoriously difficult to study in a living organism. We have thus developed a new genetic tool that allows for the inducible generation of aneuploidy in the fruit fly Drosophila melanogaster at any developmental stage. The tool is based on reversible depletion of the protein cohesin, a major regulator of fidelity of chromosome segregation during cell division. Contrary to our expectations, when larvae are challenged with organism-wide mosaic aneuploidy, they still hatch into adult flies, albeit with severe motor defects and reduced life span. While most of the developing epithelial tissues respond to aneuploidy by inducing cell death, eliminating the cells with an abnormal number of chromosomes, the developing brain does not. Most of the aneuploid neural stem cells can keep proliferating despite their abnormal chromosomal number and chromosomal instability, suggesting that these cells are uniquely resistant to aneuploidy-associated stresses. The differential tissue response led us to hypothesize that the brain is the limiting tissue in response to developmental aneuploidy. To test it, we modified the aneuploidy induction system to protect the brain from aneuploidy while the rest of the tissues were affected. As a result, we observed a complete rescue of previous motor defects and life span reduction, demonstrating that the developing brain is the tissue most susceptible to aneuploidy.