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GPR56 keeps oligodendrocyte precursor cells (OPCs) in a proliferative
state thus guaranteeing axons insulation so that they have signal strength.
Image Credit: Nature Communications (2)
A gene vital to the central nervous system
Scientists have identified a gene that helps regulate how well nerves of the central nervous system are insulated, and healthy insulation is vital for increasing the conductivity in nerve signals.
Researchers at Washington University School of Medicine in St. Louis report finding in zebrafish and mice, a gene that may have implications in human diseases where insulation is lost — such as multiple sclerosis.
The study appears Jan. 21, 2015 in Nature Communications (1).
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 by 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, researchers found that
when the protein Gpr56 is disabled, there
are too few oligodendrocytes to insulate 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 at all.
Without Gpr56, the cells responsible for
applying insulation fail to reproduce them-
selves, according to senior author Kelly R. Monk PhD, assistant professor of developmental biology. These cells actually matured too early - instead of continuing to replicate. In adulthood, there were too few mature cells, leaving many axons without insulation.
Monk and her team study zebrafish because they are excellent models of a vertebrate nervous system. Their embryos are transparent and mature outside of the fish, making it easy to observe developmental processes.
Said first author Sarah D. Ackerman, a graduate student in Monk’s lab: “We first saw this defect in the developing zebrafish embryo. 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 undermyelinated axons.”
A companion paper in Nature Communications (2), 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 has also 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.
In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs). The molecular mechanisms that govern oligodendrocyte development are incompletely understood, but recent studies implicate the adhesion class of G protein-coupled receptors (aGPCRs) as important regulators of myelination. Here, we use zebrafish and mouse models to dissect the function of the aGPCR ?Gpr56 in oligodendrocyte development. We show that ?gpr56 is expressed during early stages of oligodendrocyte development. In addition, we observe a significant reduction of mature oligodendrocyte number and myelinated axons in ?gpr56 zebrafish mutants. This reduction results from decreased OPC proliferation, rather than increased cell death or altered neural precursor differentiation potential. Finally, we show that these functions are mediated by Gα12/13 proteins and Rho activation. Together, our data establish ?Gpr56 as a regulator of oligodendrocyte development.
Mutations in ?GPR56, a member of the adhesion G protein-coupled receptor family, cause a human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Magnetic resonance imaging (MRI) of BFPP brains reveals myelination defects in addition to brain malformation. However, the cellular role of ?GPR56 in oligodendrocyte development remains unknown. Here, we demonstrate that loss of ?Gpr56 leads to hypomyelination of the central nervous system in mice. ?GPR56 levels are abundant throughout early stages of oligodendrocyte development, but are downregulated in myelinating oligodendrocytes. ?Gpr56-knockout mice manifest with decreased oligodendrocyte precursor cell (OPC) proliferation and diminished levels of active ?RhoA, leading to fewer mature oligodendrocytes and a reduced number of myelinated axons in the corpus callosum and optic nerves. Conditional ablation of ?Gpr56 in OPCs leads to a reduced number of mature oligodendrocytes as seen in constitutive knockout of ?Gpr56. Together, our data define ?GPR56 as a cell-autonomous regulator of oligodendrocyte development.
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, 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.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
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