Previous work had identified a corepressor, NAB1, which represses transcriptional activation mediated by NGFI-A (also known as Egr-1, zif268, and Krox24) and Krox20. These zinc finger transcription factors are encoded by immediate-early genes and have been implicated in a wide variety of proliferative and differentiative processes. We have isolated and characterized another corepressor, NAB2, which is highly related to NAB1 within two discrete domains. The first conserved domain of NAB2 mediates an interaction with the R1 domain of NGFI-A. NAB2 represses the activity of both NGFI-A and Krox20, and its expression is regulated by some of the same stimuli that induce NGFI-A expression, including serum stimulation of fibroblasts and nerve growth factor stimulation of PC12 cells. The human NAB2 gene has been localized to chromosome 12q13.3-14.1, a region that is rearranged in several solid tumors, lipomas, uterine leiomyomata, and liposarcomas. Sequencing of the Caenorhabditis elegans genome has identified a gene that bears high homology to both NAB1 and NAB2, suggesting that NAB molecules fulfill an evolutionarily conserved role.Transcriptional control plays a vital role in regulating fundamental cellular processes such as proliferation, differentiation, and cell death. Changes in gene expression are often effected by altering the expression level, activity, and/or nuclear localization of transcription factors that bind to promoter and enhancer regions. In addition, many transcription factors are regulated by direct interactions with other proteins which modulate the level of transcriptional activation.

Oligodendrocyte development and myelination rely on an unusual membrane-associated transcription factor that shares functional domains with bacteriophage proteins.

Myelination is essential for nervous system function. Schwann cells interact with neurons and the basal lamina to myelinate axons, using known receptors, signals and transcription factors. In contrast, the transcriptional control of axonal sorting and the role of mechanotransduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. We describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice we show that Taz is required in Schwann cells for radial sorting and myelination, and that Yap is redundant with Taz. Yap/Taz are activated in Schwann cells by mechanical stimuli, and regulate Schwann cell proliferation and transcription of basal lamina receptor genes, both necessary for proper radial sorting of axons and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells.

The identification of EGR2 mutations in patients with neuropathies and the phenotype Egr2/Krox20(-/-) have demonstrated that the Egr2 transcription factor is critical for peripheral nerve myelination. However, the mechanism by which these mutations cause disease remains unclear, as most patients present with disease in the heterozygous state, whereas Egr2(+/-) mice are phenotypically normal. To understand the effect of aberrant Egr2 activity on Schwann cell gene expression, we performed microarray expression profiling to identify genes regulated by Egr2 in Schwann cells. These include genes encoding myelin proteins and enzymes required for synthesis of normal myelin lipids. Using these newly identified targets, we have shown that neuropathy-associated EGR2 mutants dominant-negatively inhibit wild-type Egr2-mediated expression of essential myelin genes to levels sufficiently low to result in the abnormal myelination observed in these patients.

During late fetal life, Schwann cells in the peripheral nerves singled out by the larger axons will transit through a promyelinating stage before exiting the cell cycle and initiating myelin formation. A network of extra-and intracellular signaling pathways, regulating a transcriptional program of cell differentiation, governs this progression of cellular changes, culminating in a highly differentiated cell. In this review, we focus on the roles of a number of transcription factors not only in myelination, during normal development, but also in demyelination, following nerve trauma. These factors include specification factors involved in early development of Schwann cells from neural crest (Sox10) as well as factors specifically required for transitions into the promyelinating and myelinating stages (Oct6/ Scip and Krox20/Egr2). From this description, we can glean the first, still very incomplete, contours of a gene regulatory network that governs myelination and demyelination during development and regeneration. V V C 2008 Wiley-Liss, Inc. TRANSCRIPTIONAL CONTROL OF MYELINATION AND DEMYELINATIONMyelination promoting signals (discussed in other reviews in this special issue of Glia) converge on a number of transcription factors to drive the transition of immature, promyelinating proliferative cells to myelinating cells. Over the last decade, several transcription factors were found to play key roles in this transition and the execution of a transcriptional program directing myelination. These transcription factors, their regulatory relationships, and the intracellular signaling pathways that modulate their activity have been studied with growing intensity over the last few years. These studies have revealed a number of regulatory circuits that outline the contours of a gene regulatory network of myelination in the peripheral nervous system. A simplified outline of this network is depicted in Fig. 1. A myelination promoting circuit, consisting of the POU domain factors Oct6/Scip, Brn2, and Sox10 that regulate Krox20/Egr2 and drives the promyelinating to myelinating transition, forms the backbone of this regulatory network. More recently, a second cross-antagonistic circuit of Krox20/Egr2 versus cJun and Sox2 has been described that governs active demyelination following nerve trauma. In the following sections, we will discuss the different transcription factors, their mechanism of action, and their regulatory relationships.