"In the early stages of brain development prior to birth, brain stem cells, also known as neural stem cells, will differentiate into neurons," explained Larry Sherman, Ph.D., an associate scientist in the Division of Neuroscience at the Oregon National Primate Research Center and an adjunct associate professor of cell and developmental biology in the OHSU School of Medicine. "In later stages, these same stem cells suddenly start becoming glial cells, which perform a number of functions that include supporting the neurons. We wanted to find out what factors cause this switch in differentiation. We also wanted to determine if the process can be controlled and used as a possible therapy. What amazed us is that it turns out a single gene may be responsible for this incredibly important task."
The key gene that the scientists studied is called brahma-related gene-1 (Brg-1) that is found in both mice and humans. This protein had been previously studied extensively in human cancers, but not in the nervous system. To determine the precise role of Brg-1, Sherman, in collaboration with Dr. Steven Matsumoto from the Integrative Biosciences Department at the OHSU School of Dentistry, bred mice lacking the gene in the nervous system. This resulted in the development of embryos with smaller brains containing neurons but virtually no glial cells. When they isolated neural stem cells, placed them into cell culture and then removed Brg1, the cells in the culture turned into neurons but failed to differentiate into glia.
"This research shows us that in mice, Brg-1 is a critical signal that prevents stem cells from turning into neurons at the wrong time. However, since we can manipulate Brg1 expression in stem cells in culture, we now have a powerful way to generate neurons that could be used to replace cells lost in a variety of diseases and conditions that affect the brain and spinal cord. That is our next step." said Sherman. "Since the process only involves a single gene, it is highly amenable for the development of drugs targeted at promoting stem cell differentiation in the adult nervous system."
While much more research needs to be conducted, the scientists believe these findings could play a role in the development of therapies to combat a variety of diseases and conditions. For instance, Parkinson's disease is related to the loss of dopamine-producing brain cells. Scientists hypothesize that it may be possible to correctly time the expression of brg-1 in neuronal stem cells either in a culture dish or in the brain to replace the lost dopamine-producing cells. Another possibility would be the replacement of lost or damaged motor neurons in patients who have suffered brain or spinal cord damage.
This research was funded in part by the Medical Research Foundation of Oregon, the National Institute's of Health and the Christopher Reeve Paralysis Foundation.
"CRF is pleased to have provided support for this study", said Susan Howley, Director of Research and Executive Vice President, Christopher Reeve Foundation. "Identifying a gene that controls how stem cells turn into different kinds of nerve cells has important implications for clinical application in spinal cord repair strategies."
The ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International.