The oligodendrocyte-specific G-protein coupled receptor GPR17 is a cell-intrinsic timer of myelination

Nat Neurosci, 2009 · DOI: 10.1038/nn.2410 · Published: November 1, 2009

Simple Explanation

This study identifies a protein, GPR17, that acts as a timer in oligodendrocytes, the cells that make myelin in the brain and spinal cord. GPR17 slows down the process of myelination. Mice with too much GPR17 have problems with myelin formation, resembling some brain disorders. Mice without GPR17 show early signs of myelination. The researchers suggest GPR17 could be a target for new treatments to help repair myelin damage in diseases like multiple sclerosis.

Study Duration

Not specified

Participants

Mice, neural stem/progenitor cells, human MS tissues

Evidence Level

Not specified

Key Findings

1
GPR17 is restricted to oligodendrocyte lineage cells but downregulated during the peak period of myelination and in adulthood.
2
Transgenic mice with sustained GPR17 expression in oligodendrocytes exhibit stereotypic features of myelinating disorders in the CNS.
3
GPR17 knockout mice display early onset of oligodendrocyte myelination.

Research Summary

This study identifies GPR17 as a negative regulator of oligodendrocyte differentiation and myelination. Sustained expression of GPR17 inhibits oligodendrocyte maturation, while GPR17 deletion accelerates myelination. GPR17 negatively regulates oligodendrocyte differentiation by inducing nuclear localization of ID2/4, which inhibit oligodendrocyte maturation by sequestering Olig1. GPR17 is upregulated in demyelinating lesions in EAE and human MS plaques, suggesting it may play a role in remyelination arrest.

Practical Implications

Therapeutic Target

Targeted inhibition of GPR17 receptor signaling might augment remyelination by immature oligodendrocytes following pathological insults.

Understanding Myelination

GPR17 is an integral signaling component that controls the timing of oligodendrocyte differentiation and orchestrates the transition between immature and mature myelinating oligodendrocytes.

Demyelinating Diseases

GPR17 upregulation appears to be associated with demyelinating lesions induced by EAE and in MS, suggesting a potential role in the pathogenesis of these diseases.

Study Limitations

1
The physiological ligands for GPR17 are not fully elucidated.
2
It is not clear whether upregulation of GPR17 in demyelinating lesions is correlated with remyelination arrest in MS lesions.
3
Adult GPR17 null mice did not appear to exhibit a significant increase of myelinated axon fibers in the CNS, suggesting compensatory mechanisms may exist.

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