Failed Cell Division Creates 'Monster' Cells in the Developing Brain

University of Virginia School of Medicine scientists have shown how mistakes in the final step of cell division can carry serious consequences for developing brain cells. The findings offer new insight into cancer and developmental disorders, and explain what happens when the body's defenses against these errors fail.

Genes that control the cutting of the bridge between dividing cells, known as "abscission," have previously been linked to both cancer and neurodevelopmental disorders. Until now, what happens when this process goes wrong in the developing brain has not been clear.

"The early brain is a sheet of cells that look like a honeycomb. The cells need to divide rapidly to expand the sheet so they can build a brain of the right size. Every time they divide, there is a thin bridge left between them that needs to be cut," explained Noelle D. Dwyer, senior author of the study published in Molecular Biology of the Cell. 

If cells fail to cut the bridge, Dwyer added, they merge back into a single oversized cell that normally triggers its own death. When that response is blocked, the doubled cells try again to divide, fail again, and form "monster" cells that disrupt the honeycomb pattern of the sheet.

Working with lab mice, the team—led by Kaela S. Lettieri—observed striking changes in cells that botched abscission. Defective cells carried two nuclei instead of one, their outer membranes were enlarged, and the hairlike cilia acting as cellular antennae were elongated, with some cells sprouting two. 

The scientists pinpointed the protein p53 as the key cleanup mechanism, detecting abnormal cells and triggering their self-destruction. With p53 blocked, faulty cells survived, attempted division again, and ended up with multiple nuclei and multiple cilia.

"When we first examined the tissue, the abnormal changes from cells that failed abscission were present, but more subtle, likely due to the abnormal cells undergoing cell death," said Lettieri. "Therefore, when we blocked cell death and reexamined the tissue, it was striking to observe how much worse the abnormal cells became."

The team believes this cascading effect may help drive certain cancers and developmental disorders. A better understanding of the process could eventually point to treatments or prevention long before birth. 

"The developing brain seems to have specialized mechanisms of cell division to make billions of neurons in a short time window, and also a more sensitive p53 response than other organs," Dwyer said. "If we can figure out how our brains maintain such exquisite control of these processes, this could eventually help us devise treatments or prevention for all sorts of birth defects and cancers."