Researchers use lessons learned from fetal brain growth to stimulate brain repair after stroke

By Crystal Mackay

Arthur Brown, PhD, and his team at Robarts Research Institute have shown that by targeting a gene called Sox9, they can stimulate axonal growth and improve recovery after stroke.
“This research is really based on the understanding of how the nervous system gets wired in the embryo,” said Brown, associate professor Anatomy and Cell Biology, and scientist at Robarts, explaining that when the brain and nervous system are first being developed, there in an abundance of nerve sprouting.

Once it has been wired and the mature circuitry is in place, the cells respond by triggering the production of molecules called chondroitin sulfate proteoglycans (CSPGs), which prevent further growth from happening. “Where there is a ‘grow’ signal, there also has to be a ‘no grow’ signal,” he said.

That’s where Sox9 comes in.

Brown and his team have previously demonstrated that the transcription factor, Sox9, controls the expression of CSPGs, and by targeting it, they can block the ‘no grow’ signal.

By using a mouse model and knocking out Sox9, the research team demonstrated that they could promote nerve sprouting in the brain to repair damage in the brain caused by stroke.

“So what’s happening in the Sox9 knockouts is that undamaged, healthy nerve cells are projecting to nerve cells that have lost their inputs from nerve cells that were damaged by the stroke,” said Brown. “This is known to occur normally at a very low level. By blocking Sox9, we are able to enhance that process by allowing for greater regrowth.”

The study, published in the journal, Experimental Neurology, showed that by knocking out Sox9, there was more reparative axonal sprouting in the brain and also improved motor ability recovery after stroke.

Brown says this is the beginning of what will now be the exciting drug discovery phase of the research as they look for ways to target Sox9 with pharmaceuticals.

“We have already had some early success with drug-like molecules which are able to block Sox9 in tissue culture,” said Brown. “This is an important first step towards a therapy that would increase sprouting and hopefully make things better for people after stroke.”