Functional genomic analysis of oligodendrocyte differentiation.
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.
Dugas
Jason C
JC
Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA. jcdugas@alum.mit.edu
Tai
Yu Chuan
YC
Speed
Terence P
TP
Ngai
John
J
Barres
Ben A
BA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D009836:Oligodendroglia / Q000166:cytology* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D040081:Protein Array Analysis / Q000379:methods*; D040641:Quantitative Trait Loci / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology
D014157:Transcription Factors