Transient lagging chromosomes cause primary microcephaly

ABSTRACT Primary microcephaly results from the impaired neuronal progenitor proliferation, causing reduced brain size and impaired cognitive abilities. Loss of the most frequently microcephaly genes, WDR62 and ASPM , slows down poleward microtubule flux and results in transient lagging chromosomes in anaphase. Whether these defects cause primary microcephaly is unknown. Here we show that transient lagging chromosomes elicit an Aurora-B-dependent activation of 53BP1 and p21, impairing cell proliferation. Co-depletion of the microtubule depolymerase inhibitor CAMSAP1/Patronin in a WDR62 depletion background, restores normal flux rates, suppresses lagging chromosomes, and allows normal cell proliferation in human cells, while rescuing the small brain and the cognitive defects in fly larvae. We postulate that transient lagging chromosomes in anaphase and 53BP1/p21-dependent response they elicit, are a major driver of primary microcephaly.