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.
Ben graduated from the University of Melbourne in 2005 before completing a postdoc at Stanford University with Professor Ben Barres in 2009. His postdoctoral research focused on defining gene expression across the different cell types of the brain and using this information to identify novel genes involved in myelination. Through this work he identified a gene (now known as Myrf) as a critical regulator of oligodendrocyte development and myelination.
Ben is the recipient of several awards, including the Australian Neuroscience Society A.W. Campbell Award, the Australian Institute of Policy and Science Victorian Tall Poppy Award and the American Anatomical Association Young Investigators Award in Morphological Sciences.
Ben is a faculty member of the Jungers Center for Neurosciences Research, the OHSU Neuroscience Graduate Program and the Graduate Program in Biomedical Sciences “D3” hub.
Greg Duncan, Ph.D., firstname.lastname@example.org
Over the course of my Ph.D., I characterized a transgenic mouse that specifically blocked the generation of new oligodendrocytes and subsequent remyelination following myelin loss. This allowed for a novel approach to study the role of remyelination in axonal health and locomotor recovery. I have recently joined the Emery laboratory as a postdoctoral fellow and look forward to continuing research into neuron-oligodendrocyte interactions. In particular, I am highly interested in the specific means by which oligodendrocytes preserve axonal function and stability as well as the mechanisms by which neurons may compensate for prolonged demyelination. Outside of the laboratory, I enjoy hiking, hockey and relaxing with friends and family.
Tyrell Simkins, D.O., Ph.D., email@example.com
Multiple Sclerosis/Neuroimmunology Fellow
Tyrell was born in Utah, but has lived across the United States. He earned his bachelor's degree in Cellular and Molecular Biology at Boise State University in Boise, ID. He then moved east to attend Michigan State University where he earned his Ph.D. in Neuroscience and Environmental Toxicology and his medical degree, D.O. Tyrell completed his Neurology Residency at UC Davis Medical in Sacramento, CA and was elected to Chief Resident in his final year. Following residency he gladly accepted the opportunity for a Multiple Sclerosis and Neuroimmunology Fellowship at the Portland VA in conjunction with OHSU beginning July 2019.
During the fellowship, he will continue clinical diagnosis/treatment of neuroimmunologic disease and also engage in translational research in the labs of Kelly Monk and Ben Emery. He is interested in understanding the mechanisms of myelin development and remyelination with an eye towards the development of therapies for myelin preservation and restoration in human disease.
A devoted husband and father, Tyrell also enjoys athletic training, meditation, philosophy, music, the outdoors, and wood building.
Graduate Student, Neuroscience Graduate Program
Hannah received her B.S. in Cellular Molecular Biology with a minor in psychology from Humboldt State University, on the beautiful northern coast of California, in 2015. There she studied the role of asymmetric cell division of neural stem cells in the initiation and progression of glioblastoma. After graduating she joined the lab of Dr. Claudia Petritsch at UCSF as a California Institute of Regenerative Medicine (CIRM) Bridges Fellow, continuing her work on asymmetric cell division, this time in oligodendrocyte progenitor cells (OPCs). In 2016 she joined the lab of Dr. Ben Barres at Stanford University as a research technician working on creating defined culture system for microglia.
Hannah joined the Neuroscience Graduate Program in 2018 and the labs of Dr. Ben Emery and Dr. Kelly Monk in 2019. With this co-mentorship she hopes to use the combined power of zebrafish and mouse models to understand the regulation and maintenance of central nervous system myelination.
Michael graduated with a B.S. in Biology and a minor in chemistry from Purdue University in 2016. He briefly worked on the effects of mutations in gpmA on biofilm formation in S. maltophilia in the Gregory Anderson lab at IUPUI before relocating to Oregon and taking up a Research Assistant position in the Emery Lab.
Outside of the lab Michael enjoys playing music, Brazilian Jiu-Jitsu, backpacking, exploration in all its forms, and the wonderful world of amateur botany.
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.
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.