Lab overview

Glia make up around half of the cells in the human brain, supporting neurons and regulating almost every aspect of nervous system function. One of the most remarkable types of glia is the oligodendrocyte, which wraps multiple axons with spiraling layers of membrane to form myelin. This dramatically increases the speed and efficiency of action potential conduction along the myelinated axons, allowing for the complex sensory, motor and cognitive functions of the vertebrate nervous system. In addition, oligodendrocytes provide trophic and metabolic support to the axons. This means that the loss of oligodendrocytes and their myelin (as seen in diseases such as Multiple Sclerosis) both disrupts the conduction of nerve impulses and also leaves the neurons vulnerable to degeneration.

Our research seeks to uncover the molecular and cellular mechanisms controlling myelination in the CNS. In particular, we are interested in the genetic pathways that regulate the generation of oligodendrocytes and their subsequent myelination of axons. We also seek to understand how neurons and oligodendrocytes interact to ultimately determine which axons are myelinated. Finally, we aim to understand how loss of myelin impacts neuronal health and how to promote myelin repair in demyelinating disease (remyelination). Our lab uses a range of techniques including genetically modified mouse models, tissue culture, genome-wide sequencing and viral approaches to address these questions.

Transcriptional control of oligodendrocyte development

Oligodendrocytes are able to differentiate from their  progenitor cells (and even form rudimentary myelin) in the absence of neurons,  suggesting much of their development is genetically hard-wired. Our work  identified Myelin Regulatory Factor (Myrf, previously known as C11Orf9, Gm98  and MRF) as a key component of this intrinsic differentiation process. The MYRF  protein acts as a transcription factor, directly promoting the expression of  several hundred other genes that underpin the myelination of axons.

Although MYRF is a transcription factor, it is not a  straightforward one. Our lab found that MYRF is a novel example of a  membrane-associated transcription factor, being synthesized as an endoplasmic  reticulum-bound transmembrane protein that needs to be cleaved before it can  access the nucleus and bind DNA. Unexpectedly, this cleavage occurs via a  mechanism that seems to have been borrowed from viruses, with a  bacteriophage-related domain within the MYRF protein allowing it to trimerize  and then self-cleave. This makes MYRF very different from other known membrane-associated  transcription factors (such as Notch or the SREBPs), all of which require  additional proteases for their activation. Our lab published these findings in  2013 back-to-back with a paper by Dr. Yungki Park from Edward Marcott’s  laboratory, who made similar findings for the human MYRF protein. Our current  work seeks to understand why the MYRF protein undergoes such a convoluted  biogenesis and how recently described human mutations disrupt the protein’s  function. We are also seeking to understand how MYRF fits into the broader program  of CNS myelination, identifying its binding partners and gene targets in  myelinating glia.

Oligodendrocyte-axon interactions during neuroplasticity

Historically, myelination appeared to be a relatively  genetically-hardwired developmental process. It is now increasingly appreciated  that not only can myelination occur throughout much of adult life, but also that  myelination is responsive to neuronal activity. This raises the possibility  that ongoing changes to myelin represent a form of neuroplasticity. Our recent  work (with collaborators from University of Melbourne, Monash University, University of Queensland and University College London) has shown that neuronal  activity promotes the generation of new oligodendrocytes in the adult mouse brain  and that these new oligodendrocytes prefer to myelinate activated axons  compared to their less active neighboring axons. Consistent with a role for  myelination in neuroplasticity, genetically blocking new myelination (by  deleting the Myrf gene in adult oligodendrocyte progenitors) disrupts normal  motor learning. Our lab is currently using a range of in vivo techniques (viral  CRISPR, DREADDs, TRAP-Seq) to better understand how neurons, oligodendrocytes  and their progenitors interact in the adult brain during plasticity.

Oligodendrocyte-axon interactions in demyelinating disease

Myelin is destroyed in a number of human diseases, most notably Multiple Sclerosis (MS). Axonal loss is also a key feature in MS, most  likely driving the ultimate clinical progression of the disease. The exact  contributions of chronic demyelination and inflammation to axonal degeneration  remain poorly understood, however. Our lab has generated novel genetic mouse  models of chronic demyelination to better understand how neurons normally  respond to loss of their myelin and how we might be able to promote neuronal  resilience to chronic demyelination. We are also collaborating with other labs  at OHSU to use our genetically modified mouse models as preclinical models to  test novel drugs that promote myelin repair.

Publications

View full list of publications on PubMed

Carlie L. Cullen, Renee E. Pepper, Mackenzie T. Clutterbuck, Kimberley A. Pitman, Viola Oorschot, Loic Auderset, Alexander D. Tang, Georg Ramm, Ben Emery, Jennifer Rodger, Renaud B. Jolivet, Kaylene M. Young. 2021 “Periaxonal and nodal plasticities modulate action potential conduction in the adult mouse brain” Cell Reports 34(3):108641.

P. Chaudhary, G. H. Marracci, E. Calkins, E. Pocius, A. L. Bensen, T. S. Scanlan, B. Emery and D. N. Bourdette. 2021 Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE. Journal of Neuroimmunology 352:577468.

Wenxian Wang, Hyeyoung Cho, Dongkyeong Kim, Younjung Park, Ji Hwan Moon, Su Jeong, Lim Sung, Min Yoon, Michael McCane, Sue A. Aicher, Sangsoo Kim, Ben Emery, Jae W. Lee, Seunghee Lee, Yungki Park, Soo Kyung Lee. 2020 PRC2 Acts as a Critical Timer That Drives Oligodendrocyte Fate over Astrocyte Identity by Repressing the Notch Pathway. Cell Reports 32(11):108147.
    
Meredith D. Hartley, Tania Banerji, Ian J. Tagge, Lisa L. Kirkemo, Priya Chaudhary, Evan Calkins, Danielle Galipeau, Mitra D. Shokat, Margaret J. DeBell, Shelby Van Leuven, Hannah Miller, Gail Marracci, Edvinas Pocius, Tapasree Banerji, Skylar J. Ferrara, J. Matthew Meinig, Ben Emery, Dennis Bourdette, Thomas S. Scanlan. 2019 Myelin repair stimulated by CNS-selective thyroid hormone action. JCI insight 4(8):e126329.

Sarah J Garnai, Michelle L Brinkmeier, Ben Emery, Tomas S Aleman, Louise C Pyle, Biliana Veleva-Rotse, Robert A Sisk, Frank W Rozsa, Ayse Bilge Ozel, Jun Z Li, Sayoko E Moroi, Steven M Archer, Cheng-Mao Lin, Sarah Sheskey, Laurel Wiinikka-Buesser, James Eadie, Jill E Urquhart, Graeme C M Black, Mohammad I Othman, Michael Boehnke, Scot A Sullivan, Gregory L Skuta, Hemant S Pawar, Alexander E Katz, Laryssa A Huryn, Robert B Hufnagel, Genomic Ascertainment Cohort, Sally A Camper, Julia E Richards, Lev Prasov. 2019. Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice. PLoS Genetics 15(5):e1008130.

Mitew, S., Gobius, I., Fenlon, L.R., McDougall, S.J., Hawkes, D., Xing, Y.L., Bujalka, H., Gundlach, A.L., Richards, L.J., Kilpatrick, T.J., Merson, T.D., Emery, B., 2018. Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner. Nature Communications 1–16.

Duncan, G.J., Plemel, J.R., Assinck, P., Manesh, S.B., Muir, F.G.W., Hirata, R., Berson, M., Liu, J., Wegner, M., Emery, B., Moore, G.R.W., Tetzlaff, W., 2017. Myelin regulatory factor drives remyelination in multiple sclerosis. Acta Neuropathol 1–20.

McKenzie, I.A., Ohayon, D., Li, H., de Faria, J.P., Emery, B., Tohyama, K., Richardson, W.D., 2014. Motor skill learning requires active central myelination. Science 346, 318–322.

Bujalka, H., Koenning, M., Jackson, S., Perreau, V.M., Pope, B., Hay, C.M., Mitew, S., Hill, A.F., Lu, Q.R., Wegner, M., Srinivasan, R., Svaren, J., Willingham, M., Barres, B.A., Emery, B., 2013. MYRF Is a Membrane-Associated Transcription Factor That Autoproteolytically Cleaves to Directly Activate Myelin Genes. PLoS Biol 11, e1001625.

Emery, B., Dugas, J.C., 2013. Purification of Oligodendrocyte Lineage Cells from Mouse Cortices by Immunopanning. Cold Spring Harbor Protocols 2013, pdb.prot073973–pdb.prot073973.

Koenning, M., Jackson, S., Hay, C.M., Faux, C., Kilpatrick, T.J., Willingham, M., Emery, B., 2012. Myelin Gene Regulatory Factor Is Required for Maintenance of Myelin and Mature Oligodendrocyte Identity in the Adult CNS. Journal of Neuroscience 32, 12528–12542.

Emery, B., 2010. Regulation of oligodendrocyte differentiation and myelination. Science 330, 779–782.

Dugas, J.C., Cuellar, T.L., Scholze, A., Ason, B., Ibrahim, A., Emery, B., Zamanian, J.L., Foo, L.C., McManus, M.T., Barres, B.A., 2010. Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron 65, 597–611.

Emery, B., Agalliu, D., Cahoy, J.D., Watkins, T.A., Dugas, J.C., Mulinyawe, S.B., Ibrahim, A., Ligon, K.L., Rowitch, D.H., Barres, B.A., 2009. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138, 172–185.

Cahoy, J.D., Emery, B., Kaushal, A., Foo, L.C., Zamanian, J.L., Christopherson, K.S., Xing, Y., Lubischer, J.L., Krieg, P.A., Krupenko, S.A., Thompson, W.J., Barres, B.A., 2008. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. Journal of Neuroscience 344, 1252304–1252304.