Chromatin-Remodeling Factor Brg1 Is Required for Schwann Cell Differentiation and Myelination

Abstract

Schwann cells produce myelin sheaths and thereby permit rapid saltatory conductance in the vertebrate peripheral nervous system. Their stepwise differentiation from neural crest cells is driven by a defined set of transcription factors. How this is linked to chromatin changes is not well understood. Here we show that the glial transcription factor Sox10 functions in Schwann cells by recruiting Brg1-containing chromatin-remodeling complexes via Baf60a to regulatory regions of Oct6 and Krox20 genes. It thereby stimulates expression of these transcriptional regulators that then cooperate with Sox10 to convert immature into myelinating Schwann cells. The functional interaction between Sox10 and Brg1 is evident from gain- and loss-of-function studies, similar neuropathies in the corresponding mouse mutants, and an aggravated neuropathy in compound mutants. Our results demonstrate that the transcription factor-mediated recruitment of the chromatin-remodeling machinery to specific genomic loci is an essential driving force for Schwann cell differentiation and myelination.

ATP-dependent chromatin remodeling during mammalian development

“…Both Brg1 and Baf155 heterozygous mutants exhibit neural tube closure defects and exencephaly, suggesting that BAF complexes have an important and dosage-sensitive role in neural differentiation and development (Bultman et al, 2000;Kim et al, 2001). In agreement with these observations, BRG1 is required during both neuronal and glial differentiation (Marathe et al, 2013;Matsumoto et al, 2006;Weider et al, 2012;Yu et al, 2013). In the central nervous system, the differentiation of glial progenitor cells to form first immature and subsequently mature myelinating oligodendrocytes requires BRG1 (Yu et al, 2013).…”

“…This combination of transcription factor, chromatin remodeler and activating histone mark drives oligodendrocyte differentiation and myelination. In the peripheral nervous system, BAF complexes are essential for the differentiation of Schwann cells (Weider et al, 2012). Here, SOX10, a Schwann cell-and melanocyte-specific marker, interacts with BAF60A and recruits the BAF complex to enhancer regions of genes encoding the Schwann cell differentiation-specific transcription factors OCT6 and KROX20 to drive differentiation and maturation.…”

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

“…However, given the minor effect of in vivo NFkB inactivation on myelination [36], BrG1 interaction with NFkB is likely to have minor functions on SC myelination. Furthermore, while Sox10 levels are moderately [37] or not [38] affected in the absence of BrG1 in SCs, Oct6, Krox20 and P0 are virtually absent. Indeed, the BAF complex is recruited by Sox10 to the Oct6 SCE (SC enhancer [39]), the Krox20 MSE and the P0 promoter to induce Oct6, Krox20 and P0 expression [38][39][40], and thereby controls the myelination process.…”

“…The BAF complex ATPase BrG1 is required for radial sorting and myelination Ablation of BrG1 in SC precursors (using floxed Brg1 and Dhh-Cre mouse lines) prevents radial sorting and myelination [37,38]. Limpert and colleagues (2013) show that BrG1 interacts with NFkB to activate the Sox10 promoter and suggest that this mechanism controls BrG1-dependent SC 39]), the Krox20 MSE and the P0 promoter to induce Oct6, Krox20 and P0 expression [38][39][40], and thereby controls the myelination process.…”

“…Limpert and colleagues (2013) show that BrG1 interacts with NFkB to activate the Sox10 promoter and suggest that this mechanism controls BrG1-dependent SC 39]), the Krox20 MSE and the P0 promoter to induce Oct6, Krox20 and P0 expression [38][39][40], and thereby controls the myelination process.…”