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

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.

P53 independent pathogenic mechanisms contribute to BubR1 microcephaly

“…Because many microcephaly-causing genes encode proteins that are involved in faithful mitosis, studying how mitotic defects lead to microcephaly builds a greater understanding of overall microcephaly pathogenesis (Frank et al, 2000;McConnell et al, 2004;Silver et al, 2010;Chen et al, 2014;Insolera et al, 2014;Faheem et al, 2015;Marjanovic et al, 2015;Mao et al, 2016;Bianchi et al, 2017;Sgourdou et al, 2017;Little and Dwyer, 2019;Shi et al, 2019;McNeely and Dwyer, 2020;Phan et al, 2021;White et al, 2021;Martins et al, 2022;Sterling et al, 2023). In this study, cellular analysis of BubR1 cKO cortices identified a spectrum of structural abnormalities in chromosomes that are caused by the functional loss of BubR1.…”

“…Distinguishing P53 activation as a molecular mechanism for microcephaly pathology in various models provides important insight into cellular defects linked to P53 activation. For instance, when P53 activation is directly associated with mitotic defects, genetic deletion or inhibition of P53 can substantially rescue the microcephaly phenotype (Sterling et al, 2023). Alternatively, when P53 elimination solely promotes cell survival, a variety of outcomes can be observed.…”

“…P53 activation can arrest the cell cycle or initiate apoptosis to eliminate genomically unfit cells as part of its role in mitotic surveillance (Pilaz et al, 2016;Soto et al, 2017;Hafner et al, 2019;Navarro et al, 2020). Importantly, P53 activation has been observed in a variety of microcephaly models (Frank et al, 2000;Gao, et al, 2000;McConnell et al, 2004;Insolera et al, 2014;Marjanovic et al, 2015;Ghouzzi et al, 2016;Mao et al, 2016;Bianchi et al, 2017;Sgourdou et al, 2017;Little and Dwyer, 2019;Shi et al, 2019;Phan et al, 2021;White et al, 2021;Martins et al, 2022;Peek et al, 2022;Sterling et al, 2023).…”

“…In some studies, genetic deletion of Trp53 rescues cortical size, suggesting that P53 activation triggers extensive cortical cell death that leads to microcephaly (Insolera et al, 2014;Marjanovic et al, 2015;Mao et al, 2016;Bianchi et al, 2017;Little and Dwyer, 2019;Shi et al, 2019;Phan et al, 2021;Peek et al, 2022;Sterling et al, 2023). Therefore, it is plausible that mitotic disruption due to BubR1 loss may result in P53 activation and subsequent cell death.…”

Entosis: the core mechanism and crosstalk with other cell death programs

“…In summary, entosis appears to select for relative setpoints of mechanical tension in cell populations by mediating the clearance of cells with high tension by those with lower tension. In noncancer tissues, this effect may eliminate dysfunctional cells and act in a tumor-suppressive manner, for example, through a clearly established function to eliminate cells exhibiting aberrant mitosis 27 , 31 , 61 or defective polarity 23 , 61 , as well as through the observed effect of entosis on limiting transformed growth 1 , 62 . Tumor-suppressive activity has also been shown in a zebrafish model where entotic internalization was shown to limit the growth of epidermal hyperplasia 63 .…”