Primary microcephaly (MCPH) is an inborn neurodevelopmental disorder that leads to reduction of brain size in the newborns. The impaired neuronal progenitor proliferation is at the origin of this disease and it leads to impaired cognitive abilities which last throughout the lifetime of the patient. Many different genes are known to be mutated in primary microcephaly, majority of which play a role in the regulation of the mitotic spindle and cytoskeleton. Loss of the most frequently mutated microcephaly genes, WDR62 and ASPM, has been shown to cause slower poleward microtubule flux during cell division and result in transient lagging chromosomes during anaphase. The precise role of these gene loss in primary microcephaly, however, remains unknown.

In order to understand the origins of WDR62-dependent primary microcephaly and elucidate general mechanisms of cell division disruption in primary microcephaly, I investigated the mitosis and cell division in human cells and larvae of Drosophila melanogaster. In my study I found that transient lagging chromosomes lead to an Aurora B-dependent activation of 53BP1 and p21. This activation also impairs cell proliferation in human cells by prolonging the duration of the entire cell cycle. The co-depletion of a protein CAMSAP1/Patronin, which protects microtubules, together with WDR62 depletion rescues normal microtubule flux rates, prevents lagging chromosomes during cell division, and leads to normal cell proliferation in human cells.

To correlate the findings in human cell culture with microcephaly disease, I took advantage of the Drosophila melanogaster model. As it is the case in humans, WDR62 depletion in Drosophila also causes a smaller brain phenotype and decreased cognitive abilities. In the brains of Drosophila larvae, co-depletion of WDR62 together with the Camsap1 orthologue Patronin can rescue the small brain and impaired cognitive ability.

This work allows us to postulate that transient lagging chromosomes in anaphase and their 53BP1/p21-dependent response are important drivers of primary microcephaly. The elucidated mechanism suggests the importance of microtubule flux and dynamics in the regulation of neuronal progenitor proliferation. Through this study we can better understand the origins of primary microcephaly and bring us closer to therapeutic advances.