Oligodendrocyte Differentiation and Myelination in the Central Nervous System
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:
1) Signaling pathways that modulate oligodendrocyte progenitor cell migration in the developing brain. A membrane surface complex of integrins, neurotransmitter receptors and the myelin proteolipid protein mediates oligodendrocyte progenitor cell migration. Migration increases when cells are treated with neurotransmitters. How this complex functions is under investigation.
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.
Wood TL, Bercury KK, Cifelli SE, Mursch LE, Min J, Dai J, Macklin WB. mTOR: a
link from the extracellular milieu to transcriptional regulation of
oligodendrocyte development. ASN Neuro. 2013 Mar 19;5(1). doi:pii: e00108.
10.1042/AN20120092. PubMed PMID: 23421405; PubMed Central PMCID: PMC3601842.
Hu X, Schlanger R, He W, Macklin WB, Yan R. Reversing hypomyelination in
BACE1-null mice with Akt-DD overexpression. FASEB J. 2013 Jan 18. [Epub ahead of
print] PubMed PMID: 23335052.
Macklin WB. The myelin brake: when enough is enough. Sci Signal. 2010 Sep
21;3(140):pe32. doi: 10.1126/scisignal.3140pe32. PubMed PMID: 20858865; PubMed
Central PMCID: PMC3175620.
Mayer CA, Macklin WB, Avishai N, Balan K, Wilson CG, Miller MJ. Mutation in
the myelin proteolipid protein gene alters BK and SK channel function in the
caudal medulla. Respir Physiol Neurobiol. 2009 Dec 31;169(3):303-14. doi:
10.1016/j.resp.2009.09.013. Epub 2009 Oct 4. PubMed PMID: 19808102; PubMed
Central PMCID: PMC3531966.
Miller MJ, Kangas CD, Macklin WB. Neuronal expression of the proteolipid
protein gene in the medulla of the mouse. J Neurosci Res. 2009
Oct;87(13):2842-53. doi: 10.1002/jnr.22121. PubMed PMID: 19479988.
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.