Emery Lab

Abstract image for Ben Emery's lab


Lab overview

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.

Myelinating oligodendrocyte in the developing mouse optic nerve (graphic)

Lab members

Lab members

Ben EmeryBen Emery

Ph.D., University of Melbourne

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 and the OHSU Neuroscience Graduate Program.

Antointette Foster

Antointette Foster

B.S. (Psych), University of Colorado Denver

Antoinette graduated from University of Colorado Denver, majoring with a B.S. in psychology a minor in ethnic studies. She became interested in pursuing a career in neuroscience after being accepted to the competitive NIH training program 'Building Research Achievement in Neuroscience.' This program provided the opportunity to work in Dr. Kim Heindenreich's laboratory, where she completed her honors thesis focusing on the role of leukotrienes in traumatic brain injury. Antoinette joined the Emery lab in 2015, and is interested in mechanisms underlying myelination. 

AeSoon BensenAeSoon Bensen

B.S., Humboldt State 2002

AeSoon is a Senior Research Assistant in the lab and provides much of the molecular biology support for the lab's projects. She previously worked in Gary Westbrook's lab at the Vollum Institute conducting neurogenesis studies. Outside science, she runs a creative small business. 

Greg DuncanGreg Duncan

Ph.D., University of British Columbia, Canada (2018)

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.

Juan Carlos CabreraJuan Carlos Cabrera

M.D. Candidate, Oregon Health & Science University (OHSU) SOM, 2019
Masters of Clinical Research, Oregon Health & Science University (OHSU) SOM, 2019
Post-baccalaureate., University of California, Irvine (UCI) SOM, 2014
B.A., Molecular and Cell Biology. University of California, Berkeley, 2012B.A., Psychology. University of California, Berkeley, 2012

My name is Juan Carlos Cabrera. I am a medical student at OHSU, School of Medicine. I'm originally from Southern California and did my undergraduate studies at UC Berkeley. As part of the Masters in Clinical Research track, I am conducting basic science research in the Emery Lab. I am also actively involved in clinical studies through the OHSU Blood Brain Barrier Program. I am particularly interested in looking at the interaction between the immune system and the CNS in various neurological diseases. In addition to exploring a career in basic and clinical research, I am also pursuing a career as a Neurologist, potentially sub-specializing in either Neuro-Immunology or Neuro-Oncology. Recreationally, I enjoy running, exploring restaurants and breweries, and visiting my family in Mexico. I am also a big proponent for diversity and am actively involved in mentoring students from underserved or disadvantaged communities.

Projects

Projects

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.

The MYRF transcription factor is initially produced as a  transmembrane protein, self-cleaving to generate a trimeric transcription factor (graphic)


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.

Genetic fate mapping of adult generated oligodendrocytes (mGFP+) in the mouse brain during DREADD-induced neural activity. From Mitew et al. 2018 (graphic)


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.

Electron micrograph of a demyelinated optic nerve following adult ablation of the Myrf gene. A mix of actively demyelinating, fully demyelinated and remyelinating axons can be seen in one image, giving a remarkable snapshot of demyelination and repair pro

Electron micrograph of a demyelinated optic nerve following adult ablation of the Myrf gene. A mix of actively demyelinating, fully demyelinated and remyelinating axons can be seen in one image, giving a remarkable snapshot of demyelination and repair processes. Image: Jo Hill, Physiology & Pharmacology and Greg Duncan, Emery lab. Work supported by the NS061800, OHSU Neuroscience Imaging Center.

Publications

Select publications

Full list of publications at www.ncbi.nlm.nih.gov/pubmed/?term=emery+ben[author]

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.