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The Journal of Neuroscience, October 25, 2006, 26(43):10967-10983; doi:10.1523/JNEUROSCI.2572-06.2006

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Development/Plasticity/Repair
Functional Genomic Analysis of Oligodendrocyte Differentiation

Jason C. Dugas,¹ Yu Chuan Tai,³ Terence P. Speed,^2,5 John Ngai,^4,5 and Ben A. Barres¹

¹Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, and ²Department of Statistics, ³Program in Biostatistics, ⁴Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, and ⁵Functional Genomics Laboratory, University of California, Berkeley, California 94720

Correspondence should be addressed to Dr. Jason C. Dugas, Department of Neurobiology, Stanford University School of Medicine, Fairchild Building Room D206, 299 Campus Drive, Stanford, CA 94305-5125. Email: jcdugas{at}alum.mit.edu

To better understand the molecular mechanisms governing oligodendrocyte (OL) differentiation, we have used gene profiling to quantitatively analyze gene expression in synchronously differentiating OLs generated from pure oligodendrocyte precursor cells in vitro. By comparing gene expression in these OLs to OLs generated in vivo, we discovered that the program of OL differentiation can progress normally in the absence of heterologous cell–cell interactions. In addition, we found that OL differentiation was unexpectedly prolonged and occurred in at least two sequential stages, each characterized by changes in distinct complements of transcription factors and myelin proteins. By disrupting the normal dynamic expression patterns of transcription factors regulated during OL differentiation, we demonstrated that these sequential stages of gene expression can be independently controlled. We also uncovered several genes previously uncharacterized in OLs that encode transmembrane, secreted, and cytoskeletal proteins that are as highly upregulated as myelin genes during OL differentiation. Last, by comparing genomic loci associated with inherited increased risk of multiple sclerosis (MS) to genes regulated during OL differentiation, we identified several new positional candidate genes that may contribute to MS susceptibility. These findings reveal a previously unexpected complexity to OL differentiation and suggest that an intrinsic program governs successive phases of OL differentiation as these cells extend and align their processes, ensheathe, and ultimately myelinate axons.

Key words: oligodendrocyte; genomics; Affymetrix; myelin; multiple sclerosis; differentiation

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Received June 19, 2006; revised Sept. 6, 2006; accepted Sept. 11, 2006.

Correspondence should be addressed to Dr. Jason C. Dugas, Department of Neurobiology, Stanford University School of Medicine, Fairchild Building Room D206, 299 Campus Drive, Stanford, CA 94305-5125. Email: jcdugas{at}alum.mit.edu

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