Centrosomal p53-dependent checkpoint establishment during mouse development

• Applicant: Dr. Hisham Bazzi
• Subject Area: Developmental Biology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 331249414

How defects in cell division impact cell fate during development and disease is a fundamental open question in biology. Centrosomes that occupy the spindle poles and organise the spindle microtubules are important regulators of cell division. Aberrations in centrosomes in humans cause microcephaly and are also highly correlated with carcinogenesis. We have shown that the loss of centrosomes in the developing mouse causes p53-dependent but DNA damage- and aneuploidy-independent cell death. Our data and others' suggest that this is a novel p53-dependent centrosomal checkpoint that is sensed during mitosis and prevents further proliferation of cells with disrupted centrosome function. Interestingly, the mouse embryo starts the first few divisions without centrosomes which begin to form around the pre-implantation blastocyst stage (~ embryonic day, E3), but our data indicate that a checkpoint is not elicited until post-implantation epiblast formation. Consistent with this, we have recently managed to culture and propagate mouse embryonic stem cells (mESCs) that lack centrosomes and only establish the p53-dependent checkpoint upon partial differentiation. In this application, we propose to use the mESCs and the mouse embryo to decipher how the mechanism of the centrosomal checkpoint is established during mouse embryogenesis, to identify how it is suppressed in the early acentrosomal divisions, and to dissect this novel p53-dependent pathway. We will focus on the following:1) Defining the changes in the transcriptional landscape that lead to the establishment of the centrosomal checkpoint during mouse development. 2) Elucidating the centrosomal p53-dependent checkpoint in differentiating acentrosomal mESCs. Collectively, our work will provide significant insight into a novel cell cycle checkpoint that will have important implications in understanding and treating syndromes with centrosomal aberrations such as microcephaly and cancer.

• DFG Programme: Research Grants