Instituto Gulbenkian de Ciência, Oeiras, Portugal.
PLoS Biol. 2019 Feb 22;17(2):e3000016. doi: 10.1371/journal.pbio.3000016. eCollection 2019 Feb.
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.
在生物体发育过程中研究非整倍体具有很大的局限性，因为用于产生非整倍体的慢性有丝分裂扰动通常会导致致死性。我们开发了一种遗传工具，可在果蝇发育过程中以急性和时间控制的方式诱导非整倍体。这是通过可逆耗尽有丝分裂保真度的关键分子黏合蛋白来实现的。受到非整倍体挑战的幼虫孵化成成年期，表现出严重的运动缺陷，缩短了其寿命。神经干细胞尽管是非整倍体，但表现出延迟的应激反应并继续增殖，导致染色体不稳定性迅速出现，出现复杂的核型和细胞异常。值得注意的是，当其他脑细胞谱系被迫自我更新时，非整倍体相关的应激反应明显延迟。仅使发育中的大脑免受诱导性非整倍体的影响就足以挽救运动缺陷和成年期寿命，这表明神经组织最不适合应对发育性非整倍体。
