An entosis-like process induces mitotic disruption in Pals1 microcephaly pathogenesis

Entosis is a process of cell cannibalism observed in cancer. Here, Sterling and colleagues report that entosis can also play a role in brain development and can contribute to the pathogenesis of microcephaly. Entosis is cell cannibalism utilized by tumor cells to engulf live neighboring cells for pro- or anti-tumorigenic purposes. It is unknown whether this extraordinary cellular event can be pathogenic in other diseases such as microcephaly, a condition characterized by a smaller than normal brain at birth. We find that mice mutant for the human microcephaly-causing gene Pals1, which exhibit diminished cortices due to massive cell death, also exhibit nuclei enveloped by plasma membranes inside of dividing cells. These cell-in-cell (CIC) structures represent a dynamic process accompanied by lengthened mitosis and cytokinesis abnormalities. As shown in tumor cells, ROCK inhibition completely abrogates CIC structures and restores the normal length of mitosis. Moreover, genetic elimination of Trp53 produces a remarkable rescue of cortical size along with substantial reductions of CIC structures and cell death. These results provide a novel pathogenic mechanism by which microcephaly is produced through entotic cell cannibalism.

Automated summary

Entosis, a process of cell cannibalism observed in cancer, is also found to play a role in brain development and contribute to microcephaly. The study shows that mutant mice for the microcephaly-causing gene Pals1 exhibit cell-in-cell structures and abnormal mitosis, which can be eliminated by ROCK inhibition. The removal of Trp53 gene also rescues cortical size and reduces cell-in-cell structures and cell death.