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

Noelle A. Sterling, Jun Young Park, Raehee Park, Seo-Hee Cho and Seonhee Kim ()
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Noelle A. Sterling: Temple University
Jun Young Park: Temple University
Raehee Park: Temple University
Seo-Hee Cho: Thomas Jefferson University
Seonhee Kim: Temple University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-022-35719-y

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