Scientists discover protein instrumental to brain development and repair

Scientists at Children's National Medical Center have demonstrated conclusively that a specific protein and its signaling activity are instrumental in myelination and remyelination, processes essential to the creation and repair of the brain's white matter.

This groundbreaking discovery in mouse models points the way to developing treatments or interventions to enhance healthy brain development and/or brain disease repair in children and adults. The paper will be published in the August issue of Nature Neuroscience.

"By understanding the fundamental mechanisms of brain development, we get closer to finding clear instructions to repairing developmental brain disorders and injuries," said Vittorio Gallo, PhD, Director, Center for Neuroscience Research, Children's Research Institute at Children's National Medical Center.

Dr. Gallo and colleagues, study used mouse models to identify an essential protein and its signaling activity in the processes of myelination and remyelination. These processes are relevant to white matter development and repair. When white matter is injured or defective, the essential functions of information relay are impaired. Underdeveloped white matter or white matter injuries are linked to conditions including mental retardation, cerebral palsy and multiple sclerosis.

"Children's National Medical Center is the ideal environment for complex research," said Dr. Gallo."We work collaboratively with research institutes around the world, and then we walk down the hall to confer with colleagues who are on the front line of direct clinical care. My colleagues in clinical research and care pioneered whole body cooling, which slows down brain damage underway in compromised newborns. Our breakthrough at the level of laboratory research will soon translate to the bedsides where they care for newborns."

"If we can marry whole body cooling with new approaches that boost the activity of this essential protein, we may be able to slow down injury and enhance myelination," continued Dr. Gallo. 'some day we may be able to repair brain damage and subsequent affects such as mental retardation, developmental disabilities or other disorders that result from incomplete myelination or white matter damage."

Myelination in humans begins in utero at around 5 months of gestation and continues throughout the first three years of life, but can be impaired for a number of reasons, most commonly intrauterine infection, reduced or interrupted blood flow (which carries oxygen and nutrients) to the forming infant brain, or perinatal injury. These conditions affect up to 30 percent of preterm babies, many with severe motor and cognitive deficits, such as in patients affected by cerebral palsy.

Remyelination is a natural attempt by the brain to repair damage of the white matter; however the brain does not have the ability to completely repair itself.

Dr. Gallo and colleagues, work used enhanced epidermal growth factor receptor (EGFR) protein and activity to clearly demonstrate the role that this molecule plays as a catalyst to the natural processes of proliferation and migration of progenitor cells, which are integral to white matter development and repair. By first inserting enhanced EGFR protein and showing enhanced myelination/remyelination, and then using an EGFR protein with reduced biological activity , and showing the decrease in myelination/remyelination , Dr. Gallo and colleagues demonstrate that EGFR protein is an essential ingredient and that its signaling is instrumental in progenitor cell proliferation, migration, and in myelination and functional repair of white matter.

Dr. Gallo's work reported in this paper specifically demonstrates the following:

• Progenitor cells in the peri-ventricular zone of the brain contribute to remyelination of white matter lesions.
• A lesion in white matter naturally prompts progenitor cells to replicate and migrate to the site of the lesion where they are involved in remyelination and functional repair.
• Over-expression (through genetic manipulation) of epidermal growth factor receptor (EGFR) protein promotes both myelination and remyelination (creation and repair of white matter).
• Over-expression (through genetic manipulation) of EGFR protein promotes functional recovery of neural fibers (demonstrated through the conduction of electrical impulses).
• Reducing (through genetic manipulation) EGFR signaling decreases myelination and remyelination.

Dr. Gallo's work also reconfirmed that by enhancing EGFR receptor activity on a specific population of progenitor cells (through genetic manipulation), myelination and remyelination can be enhanced. This part of the study builds on earlier work done in collaboration with Nancy Ratner, PhD, Professor in the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center.