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An entosis-like process induces mitotic disruption in Pals1 microcephaly pathogenesis
Noelle A Sterling1,2, Jun Young Park1, Raehee Park1
1Shriners Hospitals Pediatric Research Center, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
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.
Insights
Entosis, a form of cell cannibalism, contributes to microcephaly by causing cell death in developing brains. Inhibiting ROCK or Trp53 can reduce these cell-in-cell structures and rescue brain size.
Area of Science:
- Cell Biology
- Developmental Neuroscience
- Pathology
Background:
- Entosis is a cellular process where live cells are engulfed by neighboring cells, observed in tumor contexts.
- The role of entosis in non-cancerous diseases, like microcephaly, remains largely unexplored.
- Microcephaly is a neurodevelopmental disorder characterized by a significantly smaller brain size.
Purpose of the Study:
- To investigate the potential role of entosis in the pathogenesis of microcephaly.
- To explore the cellular mechanisms underlying cell death in microcephaly models.
Main Methods:
- Utilized a mouse model with mutations in the microcephaly-associated gene Pals1.
- Observed cell-in-cell (CIC) structures during mitosis and cytokinesis.
- Applied ROCK inhibition and genetic elimination of Trp53.
Main Results:
- Pals1-mutant mice exhibited CIC structures and abnormal cell division in diminished cortical tissue.
- ROCK inhibition abolished CIC structures and normalized mitosis.
- Trp53 elimination rescued cortical size, reduced CIC structures, and decreased cell death.
Conclusions:
- Entosis represents a novel pathogenic mechanism contributing to microcephaly.
- Targeting entosis or related pathways may offer therapeutic strategies for microcephaly.
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