Wendy Macklin Anschutz Cell Developmental Biology

Wendy Macklin (Ph.D.)


Department of Cell & Developmental Biology


Oligodendrocyte Differentiation and Myelination in the Central Nervous System

Professor & Chair

Ph.D., Stanford University, 1979
M.S., Yale University, 1974

wendy.macklin@cuanschutz.edu
Phone: (303) 724.3426
Fax: (303) 724.3420

12801 E 17th Ave. 
Mail Stop 8108
Aurora, CO 80045

Graduate Program Affiliations

CSD
Cell Biology, Stem Cells and Development


Neuroscience Graduate Program

CNS
Center for Neuroscience

Signaling mechanisms that regulate oligodendrocyte differentiation and myelination.

This study focuses on the Akt/mTOR pathway in oligodendrocytes, which directly regulates the amount of CNS myelin. The downstream signaling pathways that control myelination are under investigation, with a focus on the impact of mTOR signaling on the cytoskeleton and endocytosis.

The impact of ischemia on actively myelinating oligodendrocytes.

Myelination is a highly energy dependent process but ischemia/reperfusion injury in juvenile mice has an unexpectedly small impact on myelinating oligodendrocytes. Gene expression pathways that are involved in protected oligodendrocytes from ischemic damage are actively being investigated.

Demyelination induced by antibodies cloned from multiple sclerosis patients.

How patient derived antibodies drive demyelination and alter remyelination is under active investigation. Gene expression in microglia is impacted in antibody-mediated demyelination, thereby altering remyelination.

Identification of small molecules that enhance oligodendrocyte differentiation.

This drug discovery project has identified compounds that enhance oligodendrocyte differentiation in cultured cells, and that enhance remyelination in demyelinated tissue slices in culture and in animals following in vivo demyelination. These projects have been supported for many years by grants from the NIH, the National Multiple Sclerosis Society and the American Heart Association.

Novgorodov S.A., Riley C.L., Keffler J.A., Yu J., Kindy M.S., Macklin W.B., Lombard D.B., Gudz T.I. SIRT3 Deacetylates Ceramide Synthases: Implications for Mitochondrial Dysfunction and Brain Injury. J Biol Chem. 291:1957-1973, 2016.  PMID: 26620563.

Li, Y., Dunphy, J., Pedraza, C.E., Lynch, C.R., Cardona, S.M., Macklin, W.B., Lynch, W.P. Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence. J. Virology 90:3385-3399, 2016. PMID: 26764005.

Ahrendsen J.R., Grewal, H.S., Hickey, S.P., Culp, C.M., Gould, E.A, Shimizu, T., Strnad, F.A., Traystman, R.J., Herson, P.S., and Macklin, W.B. Juvenile striatal white matter is resistant to ischemia-induced damage. Glia 64:1972-1986, 2016 PMID: 27463063.

Bai, CB, Sun, S, Roholt, A, Benson, E, Edberg, D, Medicetty, S, Dutta, R, Kidd, G, Macklin WB,Trapp, B. A mouse model for testing remyelinating therapies. Exp Neurol. 2016 Jul 3;283(Pt A):330-340. PMID: 27384502.

Turcotte, R., Rutledge, D.J., Belanger, E., Dill, D., Macklin W.B., Cote, D.C. Intravital assessment of myelin molecular order with polarimetric multiphoton microscopy. Sci Rep. 2016 Aug 19;6:31685. doi: 10.1038/srep31685. PMID: 27538357.

Liu, Y., Harlow, D.E., Given, K.S., Owens, G.P., Macklin, W.B., and Bennett, J.L.  Variable sensitivity to complement-dependent cytotoxicity in murine models of neuromyelitis optica, J. Neuroinflammation 13:301, 2016 PMID: 27905992.

Verden, D. and Macklin, W.B. Neuroprotection by central nervous system remyelination: Molecular, cellular and functional considerations. J. Neuroscience Research 94:1411-1420, 2016. PMID: 27618492

Hussain, R., and Macklin, W.B. Integrin linked kinase (ILK) deletion disrupts oligodendrocyte development by altering cell cycle, J. Neuroscience 37:397-412. 2017 PMID: 28077718.

Liu, Y., Given, K.S., Harlow, D.E., Matschulat, A.M., Macklin, W.B., Bennett, J.L., Owens, G.P. Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination.  Acta Neuropathol Commun. 5:25. 2017 doi: 10.1186/s40478-017-0428-PMID: 28340598. 

McLane, L.E., Bourne J.N., Evangelou E.B., Khandker L., Macklin W.B., Wood T.L. Loss of Tuberous Sclerosis Complex1 in Adult Oligodendrocyte Progenitor Cells Enhances Axon Remyelination and Increases Myelin Thickness after a Focal Demyelination. J. Neuroscience 37:7534-7546. 2017 PMID: 28694334

Ryan, D.P., Gould, E., Seedorf, G., Masihzadeh, O., Abman, S., Vijayaraghavan, S., Macklin W.B., Restrepo, D., and Shepherd, D.P. Automatic and adaptive heterogeneous refractive index compensation for light-sheet microscopy. Nature Communications 8:612 2017. PMID: 28931809

Peschl P., Schanda K., Zeka B., Given K., Böhm D., Ruprecht K., Saiz A., Lutterotti A., Rostásy, K., Höftberger R., Berger T., Macklin W., Lassmann H., Bradl M., Bennett J.L., Reindl M. Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation. 14(1):208. doi: 10.1186/s12974-017-0984-5. 2017 PMID: 29070051

Abi Ghanem C., Degerny C., Hussain R., Liere P., Pianos A., Tourpin S., Habert R., Macklin W.B., Schumacher M., Ghoumari A.M. Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor. PLoS Genet.13:e1007049, 2017. PMID: 29107990

Orfila J.E., Grewal H., Dietz R.M., Strnad F., Shimizu T., Moreno M., Schroeder C., Yonchek J., Rodgers K.M., Dingman A., Bernard T.J., Quillinan N., Macklin W.B., Traystman R.J., Herson P.S. Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke. J Cereb Blood Flow Metab. 2017 Jan 1:271678X17750761. PMID: 29283314.

Ahrendsen .J. T., Harlow D.E., Finseth L.T., Bourne J.N., Hickey S.P., Gould E.A., Culp C.M., Macklin W.B. The Protein Tyrosine Phosphatase Shp2 Regulates Oligodendrocyte Differentiation and Early Myelination and Contributes to Timely Remyelination. J Neurosci. 38:787-802, 2018. PMID: 29217681.

Gould E.A., Busquet N., Shepherd D., Dietz R.M., Herson P.S., Simoes de Souza F.M., Li A., George N.M., Restrepo D., Macklin W.B. Mild myelin disruption elicits early alteration in behavior and proliferation in the subventricular zone. Elife. 2018 Feb 13;7. pii: e34783. doi:10.7554/eLife.34783. PMID: 29436368.

Bruce K.D., Gorkhali S., Given K., Coates A.M., Boyle K.E., Macklin W.B., Eckel R.H. Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination. Front Mol Neurosci.11:57, 2018. PMID:29599706.

Rodgers K.M., Ahrendsen J.T., Patsos O.P., Strnad F.A., Yonchek J.C., Traystman R.J., Macklin W.B., Herson P.S. Endogenous Neuronal Replacement in the Juvenile Brain Following Cerebral Ischemia. Neuroscience.380:1-13, 2018 PMID: 29649514.

Liu Y., Given K.S., Owens G.P., Macklin W.B., Bennett J.L. Distinct patterns of glia repair and remyelination in antibody-mediated demyelination models of multiple sclerosis and neuromyelitis optica. Glia. 66:2575-2588, 2018 PMID: 30240044.

Preston, M.A., Finseth, L.T., Bourne, J.N., Macklin W.B. A novel myelin protein zero transgenic zebrafish designed for rapid readout of in vivo myelination.  Glia  67:650-667, 2019. PMID:30623975

Ishii A., Furusho M., Macklin W., Bansal R. Independent and cooperative roles of the Mek/ERK1/2-MAPK and PI3K/Akt/mTOR pathways during developmental myelination and in adulthood. Glia. 67:1277-1295, 2019. PMID: 30761608

Dingman, A.L., Rodgers, K.M., Dietz, R.M., Hickey, S.P., Frazier, A.P., Clevenger, A.C., Yonchek, J.C., Traystman, R.J., Macklin, W.B., Herson, P.S. Oligodendrocyte Progenitor Cell Proliferation and Fate after White Matter Stroke in Juvenile and Adult Mice. Dev Neurosci.12:1-16. 2019 PMID: 30861520.

Liu, Y., Given, K.S., Dickson, E.L., Owens, G.P., Macklin W.B., Bennett, J.L., Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp Neurol. 318:32-41, 2019.

Orfila, J.E., Grewal, H., Dietz, R.M., Strnad, F., Shimizu, T., Moreno, M., Schroeder, C., Yonchek, J., Rodgers, K.M., Dingman, A., Bernard, T.J., Quillinan, N., Macklin, W.B., Traystman, R.J., Herson P.S. Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke. J Cereb Blood Flow Metab. 39:1005-1014, 2019. PMID: 29283314

Brown, T.L. and Macklin W.B. The actin cytoskeleton in myelinating cells. Neurochemical Research, Mar 7. doi: 10.1007/s11064-019-02753-0. 2019. PMID: 30847860

Ornelas I.M., Khandker L., Wahl S.E., Hashimoto H., Macklin W.B., Wood T.L. The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation. Glia. 2020 Jan 6. doi: 10.1002/glia.23776 PMID: 31904150

Musah A.S., Brown T.L., Jeffries M.A., Shang Q., Hashimoto H., Evangelou A.V., Kowalski A., Batish M., Macklin W.B., Wood T.L. Mechanistic target of rapamycin regulates the oligodendrocyte cytoskeleton during myelination. J Neurosci. pii: JN-RM-1434-18. doi: 10.1523/JNEUROSCI.1434-18.2020. PMID: 32139584

Bargagna-Mohan P., Schultz G., Rheaume B., Trakhtenberg E.F., Robson P., Pal-Ghosh S., Stepp M.A., Given K.S., Macklin W.B., Mohan R. Corneal nonmyelinating Schwann cells illuminated by single-cell transcriptomics and visualized by protein biomarkers. J. Neurosci Res. 99:731-749  2020. PMID: 33197966

Brown T.L., Hashimoto H., Finseth L.T., Wood T.L., Macklin W.B. PAK1 positively regulates oligodendrocyte morphology and myelination. J Neurosci. 41:1864-1877, 2021. PMID: 33478987

Adams, K.L., Dahl, K.D., Gallo, V., and Macklin W.B. Intrinsic and extrinsic regulators ofoligodendrocyte progenitor proliferation and differentiation. Seminars in Cell and Developmental Biology, in press, 2020.