Washington University. US: Scientists have identified a gene that helps regulate how well nerves of
the central nervous system are insulated, researchers at Washington University School of Medicine in St. Louis report. Healthy insulation is vital for the speedy propagation of nerve cell
signals. The finding, in zebrafish and mice, may have implications for
human diseases like multiple sclerosis, in which this insulation is
lost.
The study appears Jan. 21 in Nature Communications.
Nerve cells send electrical signals along lengthy projections called
axons. These signals travel much faster when the axon is wrapped in
myelin, an insulating layer of fats and proteins. In the central nervous
system, the cells responsible for insulating axons are called
oligodendrocytes.
The research focused on a gene called Gpr56, which
manufactures a protein of the same name. Previous work indicated that
this gene likely was involved in central nervous system development, but
its specific roles were unclear.
In the new study, the researchers found that when the protein Gpr56
is disabled, there are too few oligodendrocytes to provide insulation
for all of the axons. Still, the axons looked normal. And in the
relatively few axons that were insulated, the myelin also looked normal.
But the researchers observed many axons that were simply bare, not
wrapped in any myelin at all.
Without Gpr56, the cells responsible for applying the insulation
failed to reproduce themselves sufficiently, according to the study’s
senior author, Kelly R. Monk, PhD, assistant professor of developmental
biology. These cells actually matured too early instead of continuing to
replicate as they should have. Consequently, in adulthood, there were
not enough mature cells, leaving many axons without insulation.
Monk and her team study zebrafish because they are excellent models
of the vertebrate nervous system. Their embryos are transparent and
mature outside the body, making them useful for observing developmental
processes.
“We first saw this defect in the developing zebrafish embryo,” said
first author Sarah D. Ackerman, a graduate student in Monk’s lab. “But
it’s not simply a temporary defect that only results in delayed
myelination. When I looked at fish that were six months old, I still saw
this problem of undermyelinated axons.”
In a companion paper in the same issue of Nature Communications,
senior author Xianhua Piao, MD, PhD, of Harvard University, and her
co-authors, including Monk, showed similar defects in mice without
Gpr56. In past work, Piao also has shown evidence that human defects in
Gpr56 lead to brain malformations related to a lack of myelin.
“These are nice studies that arrived at the same conclusion
independently,” said Monk, who is also with the Hope Center for
Neurological Disorders at Washington University. “Our Harvard colleagues
used mouse models while we used fish models. And Dr. Piao’s research in
human patients suggests that similar mechanisms are at work in people.”
Monk also said that Gpr56 belongs to a large class of cell receptors
that are common targets for many commercially available drugs, making
the protein attractive for further research. The investigators pointed
out its possible relevance in treating diseases associated with a lack
of myelin, with particular interest in multiple sclerosis.
“In the case of MS, there are areas where the central nervous system
has lost its myelin,” Monk said. “At least part of the problem is that
the precursor myelin-producing cells are recruited to that area, but
they fail to become adult cells capable of producing nerve cell
insulation. Now, we have evidence that Gpr56 modulates the switch from
precursor to adult cell.”
In theory, if the precursor cells can be pushed to mature into
adulthood, they may become capable of producing myelin. According to
Monk and Ackerman, possible future work includes using the zebrafish
model system as a drug-screening tool to search for small molecules that
may flip that switch.
The work led by Washington University was supported by predoctoral
fellowships from the National Institutes of Health (NIH), NS087801 and
NS079047; and by grants from the NIH, R01 NS079445; and from the Edward
J. Mallinckrodt Foundation.
Ackerman SD, Garcia C, Piao X, Gutmann DH, Monk KR. The adhesion-GPCR
Gpr56 regulates oligodendrocyte development via interactions with
G-alpha12/13 and RhoA. Nature Communications. January 21, 2015.
The work led by Harvard University was supported by grants from the
NIH, P30 HD18655, R01 NS057536, F31 NS087801, and R01 NS079445; and by
the William Randolph Hearst Fund, the Leonard and Isabelle Goldenson
Research Fellowship and the Cerebral Palsy International Research
Foundation.
Giera S, Deng Y, Luo R, Ackerman SD, Mogha A, Monk KR, Ying Y, Jeong
SJ, Makinodan M, Bialis A, Chang B, Stevens B, Corfas G, Piao X. The
adhesion G protein-coupled receptor GPR56 is a cell autonomous regulator
of oligodendrocyte development. Nature Communications. January 21,
2015.