Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex

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 was reported to be required for abscission. Mutations of 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 in abscission and brain development. KO of 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 Those that fail show a tissue-specific response: binucleate NSCs and neurons elevate , but binucleate fibroblasts do not. This leads to massive apoptosis in the brain, but not other tissues. Double KO of both and blocks apoptosis but only partially rescues brain size. This may be because of the persistent NSC cell division defects and -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. During brain growth, embryonic neural stem cells (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 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.