Two-tier transcriptional control of oligodendrocyte differentiation

Abstract

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). They differentiate from proliferative OL precursor cells that migrate from the embryonic neuroepithelium throughout the developing CNS before associating with axons and elaborating myelin. Recent research into the regulation of OL differentiation has uncovered a two-stage mechanism of transcriptional control that combines epigenetic repression of transcriptional inhibitors with direct transcriptional activation of myelin genes. This 'two-pronged' approach creates a fail-safe system of genetic control to ensure orderly and unambiguous expression of the myelination program during development and during repair of demyelinated lesions.

Figure 1

A speculative model for transcriptional activation of myelin gene expression. SOX10, thyroid hormone receptor (THR), THR-associated protein 230 (TRAP230/MED12) and OLIG1/2 might conceivably form a transcriptional activating complex that could further synergise with ZFP488 and MRF/GM98. NKX2.2 might also bind to OLIG2, although its effect on myelin gene expression is not yet clear. YY1 can activate myelin promoters but its interactions with other transcription factors are still to be clarified.

Figure 2

An intricate gene regulatory network controls OL differentiation. The crosstalk between extrinsic signals, transcription factors and chromatin modifiers determines the balance between repressive signals that inhibit OL differentiation and de-repressive signals that stimulate OL differentiation. Of all the factors described in this review, only those with two or more connections are illustrated in this figure. Red indicates repression and green represents activation. Dashed lines represent speculations; double-headed arrows indicate physical interactions. Reference numbers are marked on each pathway.