Brg1-Dependent Chromatin Remodelling Is Not Essentially Required during Oligodendroglial Differentiation

Abstract

Myelinating Schwann cells in the vertebrate peripheral nervous system rely on Brg1 (Smarca4) for terminal differentiation. Brg1 serves as central ATP-hydrolyzing subunit of the chromatin remodelling BAF complexes and is recruited during myelination as part of these complexes by the transcription factor Sox10 in Schwann cells. Here, we analyzed the role of Brg1 during development of myelinating oligodendrocytes in the CNS of the mouse. Following Brg1 deletion in oligodendrocyte precursors, these cells showed normal survival, proliferation, and migration. A mild but significant reduction in the number of oligodendrocytes with myelin gene expression in the absence of Brg1 points to a contribution to oligodendroglial differentiation but also shows that the role of Brg1 is much less prominent than during Schwann cell differentiation. Additionally, we failed to obtain evidence for a genetic interaction between Brg1 and Sox10 comparable with the one in Schwann cells. This argues that similarities exist between the regulatory networks and mechanisms in both types of myelinating glia but that the exact mode of action and the relevance of functional interactions differ, pointing to a surprising degree of variability in the control of myelination.

Brg1 directly regulates Olig2 transcription and is required for oligodendrocyte progenitor cell specification

“…Although our findings and the study by Yu and co-workers (2013) suggest that Brg1 is required for OPC specification, another study reported that Brg1 is not required for the maturation of OPCs into oligodendrocytes (Bischof et al, 2015). Furthermore, these authors reported that Brg1 is required for the induction of Sox10 expression during or shortly after OPC specification, whereas maintenance of Sox10 expression at later times is independent of Brg1.…”

“…In contrast to studies suggesting that Brg1 is required for oligodendrocyte differentiation, Bischof and co-workers (2015) recently reported that Brg1 only plays a role in regulating the number of myelinating oligodendrocytes that arise during development. This study focused on mice with conditional loss of Brg1 in committed OPCs and late progenitor cell populations.…”

“…Sox10 has been implicated in the terminal differentiation of OPCs (Stolt et al, 2002; Hornig et al, 2013). The study by Bischof et al (2015) involved conditional disruption of the Brg1 gene using mice that expressed cre under the control of the Brn4 promoter, the activity of which is first detected at E8.5 in the future di- and mesencephalon, and subsequently in other areas of the nervous system (Zechner et al, 2003). In our studies, we utilized the nestin promoter to drive cre (Matsumoto et al, 2006 and this study), while Yu and co-workers utilized mice in which cre expression was driven by the Olig1 promoter (Yu et al, 2013), both of which result in recombination in early NPC populations.…”

ATP-dependent chromatin remodeling during mammalian development

“…oligodendrocyte differentiation than it is during the differentiation of Schwann cells (Bischof et al, 2015). BAF complexes also play essential roles in neural progenitors.…”

Epigenetic control of oligodendrocyte development: adding new players to old keepers

“…Genome-wide mapping of CHD7 target sites revealed that CHD7 forms complexes with SOX10 to activate positive regulatory oligodendrocyte genes, thereby initiating the myelination program [28]. Interestingly, BRG1-dependent chromatin remodeling is dispensable during the later stage of oligodendrocyte maturation, as Brg1 deletion following lineage specification did not affect OPC proliferation, migration, or survival, with only a mild defect in differentiation [29]. These studies support the concept that once differentiation initiates heterochromatin formation, the increased difficulty for transcription factor to access DNA would require additional involvement of molecules that can recognize, bind and modify histones or DNA in order to allow changes in chromatin conformation, preceding changes in gene expression.…”