Periodic Reporting for period 4 - ChromoCellDev (Chromosome Architecture and the Fidelity of Mitosis during Development)
Reporting period: 2020-04-01 to 2021-09-30
• A multidisciplinary approach to elucidate of how sister chromatid cohesion defects evade the checkpoint mechanisms that control mitosis (Mirkovic et al Cell Rep 2015)
• A paradigm-changing view of the process of chromosome organization emphasizing how controlled resolution of chromosome entanglements is required throughout mitosis (Piskadlo et al eLife 2017)
• A quantitative analysis of cohesin decay in mitotic fidelity uncovering previously unrecognized defects associated with cohesin loss (Carvalhal et al, JCB 2018)
• The discovery that mitotic defects associated with sister chromatid cohesion loss can be recovered by inactivation of the Spindle Assembly Checkpoint (Silva et al, Curr Biol 2018)
• The finding that the developing brain is the most sensitive tissue in response to acutely-induced aneuploidy (Mirkovic et al, PlosBiol 2019)
Collectively, these findings also raised novel hypothesis for the process of chromosome organization, currently under investigation in the lab. They were also pivotal to understand how chromosomal abnormalities underlay several human pathologies, such as cancer, infertility and developmental disorders.
Finally, our ultimate goal in this project was to understand how these changes in chromosome translate in terms of organism development. We established a unique assay that allowed us to provoke chromosome random segregation in a time controlled manner. This allowed us to uncover that cell identity determines cell fate when facing unbalanced chromosome number and that the developing brain is the most critical tissue in response to aneuploidy. This holistic approach is crucial to elucidate how abnormal chromosomal organization can ultimately dictate disease outcomes.