Faculty
Wendy Macklin
Professor and Chair
Cell and Developmental Biology
Ph.D., Stanford University, 1979
M.S., Yale University, 1974
Research Interest
Oligodendrocyte Differentiation and Myelination in the Central Nervous System
UCD at Fitzsimons
RC-1 South, Room 12118
PO Box 6511, Mail Stop 8108
Aurora, CO 80045
Phone: 303-724-3426
Fax: 303-724-3420
Email: wendy.macklin@ucdenver.edu
Departmental Affiliations
Cell and Developmental Biology
Trainees
Akash George - Postdoctoral Fellow
Danette Nicolay- Postdoctoral Fellow
Carlos Pedraza - Postdoctoral Fellow
Kathryn Bercury - Graduate Student
Joshua Brahen - Professional Research Assistant
Lowry Lindsay - Professional Research Assistant
Xuan Ly - Professional Research Assistant
Graduate Program Affiliations
Cell Biology, Stem Cells, and Development (CSD)
Research
Oligodendrocyte Differentiation and Myelination in the Central Nervous System
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Our research program focuses on brain development, studying the development of the oligodendrocyte cell lineage in the central nervous system in normal, mutant and transgenic mice, rats and zebrafish. The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. The primary focus in the laboratory is on signaling pathways that regulate specification, migration and differentiation of oligodendrocytes.
The projects in the laboratory focus on several aspects of oligodendrocyte development:
2) Signaling mechanisms that regulate oligodendrocyte differentiation and myelination. This study focuses on a transgenic mouse line that overexpresses Akt in oligodendrocytes, and which hypermyelinates to a point that is pathologic. We have demonstrated that Akt signaling through mTOR directly regulates the amount of CNS myelin. The downstream signaling pathways that control this hypermyelination and the normal regulation of myelination that generates the correct amount of myelination are under investigation.
3) 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.
4) Oligodendrocyte development in transgenic zebrafish. We have generated transgenic zebrafish with EGFP-tagged oligodendrocytes. Using these zebrafish embryos, oligodendrocyte progenitor cell migration and differentiation can be imaged in vivo, and it can be manipulated experimentally. Two zebrafish projects focus on a) the role of integrin linked kinase and b) the role of retinoic acid in oligodendrocyte development.
These projects have been supported for many years by grants from the NIH and the National Multiple Sclerosis Society.
Recent Publications
Narayanan SP, Flores AI, Wang F, Macklin WB. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J Neurosci. 29:6860-70, 2009.
Flores AI, Narayanan SP, Morse EN, Shick HE, Yin X, Kidd G, Avila RL, Kirschner DA, Macklin WB. Constitutively active Akt induces enhanced myelination in the CNS. J Neurosci. 28:7174-83, 2008.
Pedraza CE, Monk R, Lei J, Hao Q, Macklin WB. Production, characterization, and efficient transfection of highly pure oligodendrocyte precursor cultures from mouse embryonic neural progenitors. Glia. 56:1339-52, 2008.
Gudz TI, Komuro H, Macklin WB. Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex. J Neurosci. 26:2458-66, 2006.
Yoshida M, Macklin WB. Oligodendrocyte development and myelination in GFP-transgenic zebrafish. J Neurosci Res. 81:1-8, 2005.
Miller MJ, Haxhiu MA, Georgiadis P, Gudz TI, Kangas CD, Macklin WB. Proteolipid protein gene mutation induces altered ventilatory response to hypoxia in the myelin-deficient rat. J Neurosci. 23:2265-73, 2003.
Mallon BS, Shick HE, Kidd GJ, Macklin WB. Proteolipid promoter activity distinguishes two populations of NG2-positive cells throughout neonatal cortical development. J Neurosci. 22:876-85, 2002.