Research Profile – A Matter of (Cell) Life and Death

Researchers are studying three genes that control and shape the cells of the nervous system.

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Researchers are unravelling how a series of genes help control the number of cells in the nervous system. Their findings could lead to strategies for repairing brain tissue damaged by trauma or conditions such as Alzheimer's disease.

The development and maintenance of brain cell tissue is controlled by the interactions of three key genes in the p53 family – p53, p63 and p73. According to Dr. David Kaplan, a senior scientist at the Hospital for Sick Children, these three genes do a constant dance of life and death.

In studies on mice, Dr. Kaplan and his colleague Dr. Freda Miller have discovered that p73 is important during the early growth of the peripheral nervous system (the part of the nervous system outside the brain and spinal cord).

"Many of those nerves need this gene to survive during development," says Dr. Kaplan.

This gene also helps protect nerve cells, both inside and outside the brain, from injury – such as damage caused by anticancer drugs or Alzheimer's disease. Dr. Kaplan refers to p73 as a 'life gene' for nerves.

The p53 and p63 genes, on the other hand, are considered 'death genes'. They control how many nerve cells outside the brain survive during early development.

"[The peripheral nervous system] makes twice as many nerve cells as it needs. It's like a sculptor; it starts off with a lump of clay, then it sculpts it into a beautiful looking and optimally functioning nervous system. Your body gets rid of the nerve cells it doesn't really need. The way it does that is through the p53 and p63 genes," says Dr. Kaplan. "What we found is the three p53 family members collaborate and talk to each other to sculpt your nervous system to make the right amount of nerves."

The p73 gene also appears to be important in controlling the number of cells in the brain. The researchers found that mice born with half the normal amount of p73 genes were healthy in their youth, but as they aged, their brain function deteriorated in a manner resembling Alzheimer's disease. Mice starting with normal levels of p73 continued to have healthy brains as they aged.

In addition, the brain contains small pockets of undeveloped cells called stem cells, which the body can use to create new cells with specific functions. If researchers can find a way to trigger stem cells in the brain to grow and develop in the right way, they may be able to repair damaged brain tissue. According to Dr. Kaplan, there is evidence that p63 and p73 influence the number of new cells that are made from stem cells in the adult brain.

The researchers are now investigating an existing medication believed to help protect brain tissue. The drug, called metformin, is used by people with Type 2 diabetes. Research shows that diabetics who use the drug have lower rates of dementia. In mice, the researchers found that it activated stem cells and improved learning and memory.

The researchers have planned a clinical trial to see whether the drug can lead to improved brain function in children with brain injuries.

"[The peripheral nervous system] makes twice as many nerve cells as it needs. It's like a sculptor; it starts off with a lump of clay, then it sculpts it into a beautiful looking and optimally functioning nervous system."
– Dr. David Kaplan, Hospital for Sick Children