Summary: Research reveals a crucial role for the protein Cep55 in brain development and in abscission, the final step of cell division.
Source: University of Virginia
Researchers at the University of Virginia School of Medicine report new insights into how the brain develops, showing that the final step of cell division—abscission—is essential for achieving normal brain size and organization.
Their work identifies Cep55, a coiled-coil protein, as a key regulator of abscission in neural stem cells. The findings point to Cep55 as a potential contributor to microcephaly, a congenital condition in which the head and brain are abnormally small. Microcephaly can carry lifelong effects, including learning and developmental delays, sensory impairments, and motor difficulties. In the United States, estimates suggest the condition affects between 1 in 800 and 1 in 5,000 children annually.
“By clarifying genetic causes of microcephaly, including rare mutations, we also gain tools to understand how certain viral infections—such as Zika virus or cytomegalovirus—may lead to this condition,” said Noelle D. Dwyer, PhD, from UVA’s Department of Cell Biology.
How abscission shapes brain growth
Dwyer and colleagues focused on abscission, the last phase of cytokinesis when a newly formed daughter cell severs its connection to the mother cell. Previous cell-line studies suggested Cep55 is required for successful abscission. To test this in a developing brain, the team examined mice lacking Cep55.
Surprisingly, many neural stem cells (NSCs) were still able to complete abscission without Cep55, but the process was slower and failure rates rose markedly. Crucially, NSCs that failed to complete abscission activated a tissue-specific response: they triggered a p53-dependent program of programmed cell death (apoptosis). This robust quality-control mechanism removed large numbers of affected cells from the developing brain, producing severe microcephaly in the Cep55-deficient mice.
The researchers note that this strong apoptotic response appears specific to neural stem cells. Cells in other tissues with failed abscission, such as fibroblasts, did not mount the same p53-dependent removal program. “Neural stem cells in the prenatal brain tolerate less damage; they sacrifice themselves to avoid producing abnormal neurons or potentially tumorigenic cells,” Dwyer explained. “Other tissues show a higher tolerance for damaged cells and do not trigger this immediate cell-death response.”
When the team blocked the NSC death signal genetically, brain size in the mice increased relative to Cep55 knockout alone, but only partially returned toward normal. Even with reduced apoptosis, brain architecture and function remained disrupted. That outcome indicates that timely, successful abscission is required not only to preserve cell numbers but also to maintain correct brain organization and function.
Dwyer cautioned that therapeutic strategies that inhibit cell-death pathways—whether by drugs or gene therapy—might increase brain size in some forms of microcephaly but could also worsen overall brain function. “These approaches must be tested carefully in animal and cell-culture models before considering clinical application,” she said.
The UVA findings align with clinical observations: human mutations in the CEP55 gene produce severe brain and central nervous system malformations, while other organs are comparatively spared. The new experimental work offers a mechanistic explanation for that tissue-specific vulnerability.
Beyond developmental disorders, the study has implications for cancer research. Cep55 alterations are associated with several human cancers, and understanding Cep55’s normal role in cell division helps explain how its dysfunction could promote aberrant division and tumor growth.
Key contributors to this research include Jessica Little and Katrina McNeely, who completed their PhDs in Dwyer’s laboratory. The study’s team also included Nadine Michel, Christopher J. Bott, Kaela S. Lettieri, Madison R. Hecht, and Sara A. Martin. Little and McNeely are co-first authors.
The full findings appear in the Journal of Neuroscience under the title: “Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex.”
Funding: This work was supported by the National Institutes of Health (grants RO1NS076640, R21NS106162, R01HD102492 and F30HD093290) and a UVA Cell and Molecular Biology Training Grant (T32GM008136).
About this brain development research news
Source: University of Virginia
Contact: Josh Barney – University of Virginia
Image: The image is in the public domain
Original Research: Closed access. “Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex” by Jessica N. Little, Katrina C. McNeely, Nadine Michel, Christopher J. Bott, Kaela S. Lettieri, Madison R. Hecht, Sara A. Martin and Noelle D. Dwyer. Journal of Neuroscience.
Abstract
Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex
Embryonic neural stem cells (NSCs) must regulate many polarized cell divisions to build the cortex. Cytokinetic abscission severs daughter cells at the apical membrane, a process mediated by the midbody. In cultured cell lines, Cep55 has been reported as necessary for abscission, and human CEP55 mutations are linked to cortical malformations. Its role in specialized NSC divisions was unclear.
Using Cep55 knockout mice, the researchers show that loss of Cep55 causes abscission defects in multiple cell types and leads to postnatal lethality. The brain is disproportionately affected, producing severe microcephaly at birth. Quantitative analyses in fixed and live cortical NSCs indicate Cep55 accelerates and improves abscission by aiding ESCRT recruitment and timely microtubule disassembly.
Most NSCs eventually complete abscission without Cep55, but a subset fail and become binucleate. Those neural cells elevate p53 and undergo widespread apoptosis; by contrast, binucleate fibroblasts do not induce p53 and are not broadly eliminated. Double knockout of p53 and Cep55 blocks apoptosis but only partially rescues brain size, likely because of persistent division defects and p53-independent premature cell-cycle exit.
These results support emerging evidence that abscission regulation and tolerance for division errors vary by cell type, and that stringent control of abscission is particularly critical for neural stem cells building the brain.
SIGNIFICANCE STATEMENT
During brain growth, embryonic NSCs divide repeatedly. In the final step, abscission severs the daughter from the mother cell. Cep55 is implicated in recruiting factors required to complete this process. Cep55 mutants develop very small, structurally abnormal brains while other organs remain nearly normal. NSC abscission can proceed without Cep55 but is slower and fails more often; when failures occur, NSCs trigger p53-dependent apoptosis, whereas non-neural cells do not. Blocking this apoptotic signal only partially restores brain growth, highlighting that precise regulation of abscission is essential for healthy brain development.