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UNIGE scientists show how mutating a single gene can slow down cell division and lead to an unusually small brain.
A depiction of a normally developed brain compared to a brain with microcephaly. © All rights reserved
Human birth requires billions of cells to divide from a fertilized egg to a baby. With each of these divisions, the genetic material of the mother cell doubles in order to be evenly distributed between the two new cells. In primary microcephaly, a rare but serious genetic disorder, the ballet of cell division is dysregulated and prevents the brain from properly developing. Scientists from the University of Geneva (UNIGE), in collaboration with Chinese scientists, have shown how the mutation of a single protein, WDR62, prevents the proper formation of the cable network that is responsible for separating the genetic material into two parts. Since cell division is then slowed down, the brain does not have time to fully rebuild. These results, which can be read in the Journal of Cell Biology, shed new light on cell division, a phenomenon that is also involved in the development of cancer.
Cell division is an essential mechanism for the development of any new being. It is precisely regulated and requires coordination and control. For this purpose, cables called “microtubules†enable the genetic material packaged in chromosomes to be evenly distributed between the two daughter cells. “These microtubules are constantly assembling and disassembling in order to reach their correct size at any time,†explains Patrick Meraldi, Professor in the Department of Cell Physiology and Metabolism at the Medical Faculty of UNIGE and coordinator of the Translational Research Center in Onco-haematology (CRTOH ). who directed this work. “To regulate their size, the cell uses a protein, katanin (from the Japanese katana for sword), which is responsible for cutting microtubules to the correct length.”
A small mutation with serious consequences
A mutation of any of the genes involved in cell division is enough to cause an abnormally small brain and serious neural problems, greatly reducing the autonomy of those affected. Primary microcephaly is often associated with blood relatives and affects between 1 in 30,000 and 1 in 250,000 people, depending on the region of the world.
But how can a single mutation have such serious consequences? And why, if the mutated gene is so important, is it only affecting brain development? The first clues to answering these questions came a few years ago when scientists discovered that the most commonly mutated gene in microcephaly, ASPM, is involved in the location and function of katanin, the molecular sword responsible for cutting through microtubules. “But was this the core mechanism of microcephaly or just specific to this mutation?†Asked Amanda Guerreiro, postdoc in Patrick Meraldi’s laboratory and lead author of the study.
Katanin, an essential molecular sword
In vitro experiments with cell lines showed that the second most common gene involved in microcephaly, WDR62, like ASPM, is required for katanin to localize and function. Similarly, scientists observed that if katanin is not in the right place at the right time, the microtubules become too long. Because space is limited, they will compress and become S-shaped rather than straight and stretched. When microtubules have to pull chromosomes to distribute them evenly in the two new cells, the tension is not strong enough and some chromosomes lag behind others. A slight dysregulation in the mechanics of cell division is sufficient to slow down the distribution of the chromosomes. Since this delay is viewed as a fatal error by the cells, many will die. The death of too many cells would then lead to an unusually small brain size in people with primary microcephaly.
“Katanin seems to be the central mechanism of this developmental disease,” says Patrick Meraldi. “The result of our work, however, is much more comprehensive: It enables us to understand how cancer cells change the system so that they can endlessly divide and multiply in the body.”
Video showing normal cell division.
Video showing a division in which some chromosomes are delayed.
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