Developmental function of transcription factor conserved in human white matter disorders
Some neurological conditions such as multiple sclerosis and cerebral palsy are associated with the inability to repair the chronic destruction of myelin sheaths that surround the core of a nerve fiber and function to speed transmission of nerve impulses.
To better understand the failure to remyelinate these nerves in disorders involving loss of these sheaths, researchers at Baylor College of Medicine examined how myelin forms during development. They found that a transcription factor known as NFIA plays a key role in this developmental process. The findings, which appear in the Annals of Neurology, also show that NFIA acts similarly during those demyelinating diseases.
"We already know that within these disease states, oligodendrocyte precursors, or immature cells with the capacity to become the cells that are responsible for generating myelin sheaths, are recruited to the lesion site. However, something stops those precursors from becoming a mature myelinating cell," said Dr. Stacey M. Glasgow, postdoctoral fellow in the Center for Cell and Gene Therapy at BCM, The Methodist Hospital and Texas Children's Hospital and co-author of the study. "So we investigated how myelinating cells are formed during development to gain insights into what is inhibiting this process during the disease state."
Researchers followed NFIA expression throughout development and discovered that NFIA is present in oligodendrocytes precursors, but it is not present in the differentiated, myelinating oligodendrocytes in the developing spinal cord. In other words, NFIA is important for the initial push toward the oligodendrocyte cell fate but is not involved in the final maturation of these cells and may in fact block this process.
Overexpression of NFIA
Using cell culture, chick, and mouse model systems the researchers found that overexpression of NFIA did indeed blocked the production of mature myelinating cells, but did not affect the amount of precursor cells. Moreover, in mice lacking NFIA mature oligodendrocyte cells prematurely appeared in the spinal cord.
"These results demonstrated that NFIA is important not only for the initial specification of oligodendrocytes precursors but is also crucial for the proper timing of oligodendrocyte maturation during development," said Dr. Ben Deneen, assistant professor of neuroscience at BCM and senior author on the study.
"Next, we wanted to know if this transcription factor acts the same way in human white matter disorders, like multiple sclerosis and cerebral palsy. Normally when you have a demyelinating event, there are mechanisms that can aid in repair. But in diseases such as MS, there is stalled or halted repair, which led us to believe NFIA was acting in the same manner during the disease state as it does during development."
In collaboration with University of California San Francisco, Deneen reviewed these types of disorders and discovered that the developmental expression patterns of NFIA are conserved in multiple sclerosis and pediatric hypoxia ischemia encephalopathy. Furthermore, in a mouse model of demyelination overexpression of NFIA inhibited the repair of the demyelinated axons.
"It would appear that modulating NFIA may help to repair damage caused by these diseases, but at this point, there are too many other mechanisms that are at play that could also be affecting the repair process. We need to better understand how NFIA function fits into the context of a demyelinated lesion," said Deneen. "Nevertheless, this does give us a new direction to seek out treatment targets in future studies."
Others who contributed to the work include Dr. Stephen P. J. Fancy and Dr. David H. Rowitch (Howard Hughes Medical Investigator), both with the University of California, San Francisco, and Meggie Finley, Center for Cell and Gene Therapy.
Funding for the study came from the National Multiple Sclerosis Society, the Gillson Longenbaugh Foundation and the National Institutes of Health.