Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex
Open Access
- 23 February 2021
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 41 (15), 3344-3365
- https://doi.org/10.1523/jneurosci.1955-20.2021
Abstract
To build the brain, embryonic neural stem cells (NSCs) tightly regulate their cell divisions, undergoing a polarized form of cytokinesis that is poorly understood. Cytokinetic abscission is mediated by the midbody to sever the daughter cells at the apical membrane. In cell lines, the coiled-coil protein Cep55 was reported to be required for abscission. Mutations of Cep55 in humans cause a variety of cortical malformations. However, its role in the specialized divisions of NSCs is unclear. Here, we elucidate the roles of Cep55 in abscission and brain development. Knockout of Cep55 in mice causes abscission defects in neural and non-neural cell types, and postnatal lethality. The brain is disproportionately affected, with severe microcephaly at birth. Quantitative analyses of abscission in fixed and live cortical NSCs show that Cep55 acts to increase the speed and success rate of abscission, by facilitating ESCRT recruitment and timely microtubule disassembly. However, most NSCs complete abscission successfully in the absence of Cep55. Those that fail show a tissue-specific response: binucleate NSCs and neurons elevate p53, but binucleate fibroblasts do not. This leads to massive apoptosis in the brain, but not other tissues. Double knockout of both p53 and Cep55 blocks apoptosis but only partially rescues Cep55 -/- brain size. This may be due to the persistent NSC cell division defects and p53-independent premature cell cycle exit. This work adds to emerging evidence that abscission regulation and error tolerance vary by cell type and are especially crucial in neural stem cells as they build the brain. SIGNIFICANCE STATEMENT During brain growth, embryonic neural stem cell (NSCs) must divide many times. In the last step of cell division, the daughter cell severs its connection to the mother stem cell, a process called abscission. The protein Cep55 is thought to be essential for recruiting proteins to the mother-daughter cell connection to complete abscission. We find that Cep55 mutants have very small brains with disturbed structure, but almost normal size bodies. NSC abscission can occur, but it is slower than normal, and failures are increased. Furthermore, NSCs that do fail abscission activate a signal for programmed cell death, whereas non-neural cells do not. Blocking this signal only partly restores brain growth, showing that regulation of abscission is crucial for brain development.Keywords
Funding Information
- HHS | NIH | National Institute of Neurological Disorders and Stroke (NS076640, NS1006162)
- HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD093290, HD102492)
This publication has 66 references indexed in Scilit:
- Midbody assembly and its regulation during cytokinesisMolecular Biology of the Cell, 2012
- Proliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviourNature Communications, 2011
- Dynamics of endosomal sorting complex required for transport (ESCRT) machinery during cytokinesis and its role in abscissionProceedings of the National Academy of Sciences, 2011
- A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotypeNeural Development, 2011
- Plk1 negatively regulates Cep55 recruitment to the midbody to ensure orderly abscissionThe Journal of cell biology, 2010
- Spastin Couples Microtubule Severing to Membrane Traffic in Completion of Cytokinesis and SecretionTraffic, 2008
- Midbody Targeting of the ESCRT Machinery by a Noncanonical Coiled Coil in CEP55Science, 2008
- Differential requirements for Alix and ESCRT-III in cytokinesis and HIV-1 releaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesisThe EMBO Journal, 2007
- Cep55, a Microtubule-bundling Protein, Associates with Centralspindlin to Control the Midbody Integrity and Cell Abscission during CytokinesisMolecular Biology of the Cell, 2006