University of Virginia School of Medicine scientists have revealed how mistakes in the final step of cell division can have dire consequences for developing brain cells. The findings offer important new insights into cancerand developmental disorders, helping explain how the body tries to protect itself and what happens when it can't.
Genes that control the process of cutting the bridge between dividing cells, called "abscission," have already been linked to both cancer and neurodevelopmental disorders. But until now, scientists have been uncertain exactly what happens when abscission goes wrong in the developing brain. UVA's new insights will help researchers in their efforts to develop new ways to prevent the harmful effects of abscission mistakes.
"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 researcher Noelle D. Dwyer, PhD, of UVA's Department of Cell Biology, the UVA Brain Institute and UVA Comprehensive Cancer Center. "If the cells fail to cut the bridge, they merge back together into one big cell, which normally undergoes cell death. What we show in this paper is that if we prevent the death of these double-size cells, they will try again to divide but fail again and form a giant 'monster' cells within the cell sheet, disrupting the honeycomb pattern."
Dangerous Consequences of Abscission Errors
Cell division is an essential process for all living things. It's how our bodies form, how we grow, how we reproduce, how we repair damaged tissue. Abscission is the final step in the process, and it's at that moment that the new cells split apart. During abscission, the last tiny bridge linking the "daughter" cells is severed, and it's critical that everything goes right.
Dwyer and her team, spearheaded by UVA's Kaela S. Lettieri, looked at the consequences of abscission mistakes in cells that form the developing brain. Working with lab mice, they found that these mistakes caused dramatic changes in the new cells. Instead of a single nucleus – the cell's control center – the defective cells had two. The cells' exterior membranes were enlarged, and the hairlike structures (or "cilia") that act as cellular antenna were elongated. Further, some cells had two cilia.
The scientists identified a particular protein, called p53, that does cleanup duty in response to abscission mistakes. Our bodies manufacture this protein to detect damaged DNA or abnormal cells, and it causes the faulty cells to self-destruct. When the researchers blocked the p53 protein, the abnormal cells survived, tried and failed again to divide, and became even more faulty with multiple nuclei and multiple cilia, disturbing the regular honeycomb pattern of the sheet of cells. The researchers believe this multiplying mistake may be driving cancer tumors and developmental disorders.
"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, a graduate student in UVA's cell and developmental biology PhD program. "Therefore, when we blocked cell death and reexamined the tissue, it was striking to observe how much worse the abnormal cells became."
Based on their results, the UVA scientists conclude that the p53 protein can act as a powerful guardian of the growing brain structure by triggering double-size cells to self-destruct. But they also found that there are alarming effects if it fails – effects that cascade over time. By targeting this process, researchers eventually may be able to create treatments to stop certain cancers in their tracks, or to prevent neurodevelopmental disorders 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."
Improving our understanding of cancer and finding new ways to treat and prevent it is a primary mission of UVA Comprehensive Cancer Center, one of only 57 cancer centers in the nation to earn the National Cancer Center's "comprehensive" designation in recognition of their outstanding patient care and cutting-edge cancer research programs.
The UVA Brain Institute, meanwhile, brings together top experts from across the University to improve our understanding of the brain and address key problems in neuroscience for the betterment of people across Virginia and around the world.
Findings Published
The researchers have published their findings in the scientific journal MBoC, Molecular Biology of the Cell . The research team consisted of Lettieri, Katrina C. McNeely and Dwyer. The scientists have no financial interest in the work.
The research was supported by the National Institutes of Health, grants R01NS076640 and R01HD102492, and the UVA Brain Institute.
To keep up with the latest medical discoveries from the UVA School of Medicine and UVA's Paul and Diane Manning Institute of Biotechnology, bookmark the Making of Medicine blog at https://makingofmedicine.virginia.edu.
