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.

On the role of p53 in the cellular response to aneuploidy

“…In our experiments, the 24-h MPS1i treatment did not induce DNA damage, although we cannot rule out that continued propagation of aneuploid cells in organotypic cultures could lead to DNA damage and p53 activation at a later time. Responses to aneuploidy induction in the Drosophila brain varied in different cell types and at different times ( Mirkovic et al, 2019 ). The different p53 response observed in our study was also unlikely to be due strictly to a 2D versus 3D culturing system because 3D cultures of HCT116 cells showed a similar p53 response to those cultured in 2D.…”

Tissue stem cells: the new actors in the aneuploidy field

“…For example, mutants for the SAC gene mad2 are viable even though aneuploidy has been detected in adult tissues [33,34] and mutants for the SAC gene mps1 show a small percentage of adult viability and aneuploidy has also been detected in adult tissues of these flies [34,35]. Furthermore, strategies where aneuploidy is induced in larvae in an acute and timely controlled manner also confirm that this is compatible with adult survival [36].…”

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

“…This heterogeneity complicates separating the stresses triggered by the ongoing CIN and those triggered by the random aneuploidies provoked by CIN. One solution to this problem is to engineer models for reversible CIN, for instance, as previously done in Drosophila [30], which allows to uncouple the aneuploidy and CIN response in vivo.…”