Department of Cell and Developmental Biology (CDB)

Oligodendrocyte Differentiation and Myelination in the Central Nervous System

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.

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.

Latest Publications in PubMed