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

• Published in: Nature communications Vol. 14; no. 1; pp. 82 - 10
• Main Authors: Sterling, Noelle A., Park, Jun Young, Park, Raehee, Cho, Seo-Hee, Kim, Seonhee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/2; 13/51; 14; 14/19; 147/143; 38; 42; 42/34; 45; 49; 59; 631/378/2571/1696; 631/378/2571/2579; 631/80/304; 631/80/82/2168; 64/60; Abnormalities; Animals; Apoptosis; Brain; Cannibalism; Carcinogenesis; Cell death; Cell Nucleus; Cytokinesis; Entosis - physiology; Humanities and Social Sciences; Humans; Mice; Microcephaly; Microcephaly - genetics; Microencephaly; Mitosis; Mitosis - genetics; multidisciplinary; Pathogenesis; Plasma membranes; Science; Science (multidisciplinary); Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35719-y

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. 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.