Myelin regulatory factor

Myelin regulatory factor (MyRF), also known as myelin gene regulatory factor (MRF), is a protein that in humans is encoded by the MYRF gene.

Orthologs

Myelin regulatory factor is encoded by the Myrf/GM98 gene in mice and by the MYRF gene in humans.^[1] The family of MyRF-like-proteins also contains the orthologues pqn-47 from C. elegans and MYRFA from Dictyostelium.^[2] All orthologs have a DNA-binding domain of high homology to the Saccharomyces cerevisiae protein Ndt80 (a p53-like transcription factor) and therefore likely act as a transcription factor.

Function

MyRF is a transcription factor that promotes the expression of many genes important in the production of myelin.^[3] It is therefore of critical importance in the development and maintenance of myelin sheaths.^[4]

The expression of MYRF is specific to mature, myelinating oligodendrocytes in the CNS.^[5][6] It has been shown to be critical for the maintenance of myelin by these cells. Following ablation of MYRF the expression of myelin genes such as PLP1, MBP, MAG and MOG drops rapidly.^[4] Therefore, MYRF is a key regulator and likely a direct activator of the expression of these genes.^[3]

Animal models

Mice that lose MYRF during adulthood present with a severe demyelination similar to that seen in animal models of multiple sclerosis. This underlines the importance of an active renewal of proteins in the myelin sheath. Further, the activity of MYRF increases during remyelination, suggesting it has a critical role in this process.^[4] Animals with repressed Myrf in a proportion of oligodendrocyte precursor cells showed a delayed functional recovery from spinal cord injury.^[7]

Myrf has been shown to be significantly downregulated in a mouse model carrying the same mutation in the NPC1 protein that is underlying Niemann-Pick type C1 disease, a neurodegenerative process in which dysmyelination is a main pathogenic factor. A perturbation of oligodendrocyte maturation and myelination therefore might be an underlying reason for the neurological deficits.^[8]

References

1. "MYRF". Universal Protein Resource (UniProt) Consortium. Retrieved 2012-06-13.
2. Senoo H, Wang HY, Araki T, Williams JG, Fukuzawa M (2012). "An orthologue of the Myelin-gene Regulatory Transcription Factor regulates Dictyostelium prestalk differentiation". Int. J. Dev. Biol. 56 (5): 325–32. doi:10.1387/ijdb.120030jw. PMC 3586673. PMID 22811266.
3. Bujalka H, Koenning M, Jackson S, Perreau VM, Pope B, Hay CM, Mitew S, Hill AF, Lu QR, Wegner M, Srinivasan R, Svaren J, Willingham M, Barres BA, Emery B (September 2013). "MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes". PLoS Biol 11 (8): e1001625. doi:10.1371/journal.pbio.1001625.
4. Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B (September 2012). "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". J. Neurosci. 32 (36): 12528–42. doi:10.1523/JNEUROSCI.1069-12.2012. PMID 22956843.
5. Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, Ibrahim A, Ligon KL, Rowitch DH, Barres BA (July 2009). "Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination". Cell 138 (1): 172–85. doi:10.1016/j.cell.2009.04.031. PMC 2757090. PMID 19596243.
6. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (January 2008). "A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function". J. Neurosci. 28 (1): 264–78. doi:10.1523/JNEUROSCI.4178-07.2008. PMID 18171944.
7. Duncan GJ, Plemel JR, Hilton BJ, Liu J, Kramer JK, Kim J, Mao S, Tetzlaff W (October 2012). Myelin gene regulatory factor knockout delays functional recovery from spinal cord injury. Neuroscience 2012. pp. S60–S60.
8. Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, Köhling R, Rolfs A, Luo J (December 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metab Brain Dis 26 (4): 299–306. doi:10.1007/s11011-011-9263-9. PMID 21938520.