Functional Genomic Analysis of Oligodendrocyte Differentiation

Abstract

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.

Anti-Muscarinic Adjunct Therapy Accelerates Functional Human Oligodendrocyte Repair

“…As expected, we found several receptors with known function in rodent OPCs that were highly expressed by their human homologs (Table 2). Among these, we selected CHRM3, muscarinic M 3 R receptor, for functional validation on the basis of particularly high expression in this dataset and strong downregulation during oligodendrocyte differentiation of human CD140a ϩ cells and rat A2B5-sorted progenitors (Dugas et al, 2006). We confirmed differential expression of CHRM3 mRNA in human CD140a …”

Differential and cooperative actions of Olig1 and Olig2 transcription factors on immature proliferating cells after contusive spinal cord injury

“…Transcriptional regulation plays an important role in the differentiation of OL lineage cells from initial GPCs to fully mature myelinating OLs (Dugas et al, 2006;Nicolay et al, 2007). Previous studies showed that a pair of related basic helix-loop-helix transcription factors, Olig1 and Olig2, is essential for generating OL lineage cells (Lu et al, 2000;Zhou and Anderson, 2002).…”

Phosphodiesterase-Iα/autotaxin's MORFO domain regulates oligodendroglial process network formation and focal adhesion organization

“…Our previous studies identified phosphodiesterase-Iα/autotaxin (PD-Iα/ATX), also designated pyrophosphatase/phosphodiesterase 2 (NPP2), as a protein that is released by post-migratory, premyelinating oligodendrocytes during the developmental stages of initial myelination (Fuss et al, 1997;Fox et al, 2003; see also Dugas et al, 2006;Nielsen et al, 2006;Savaskan et al, 2006). Functionally, PD-Iα/ATX possesses active adhesion-antagonizing, i.e.…”