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

Abstract

The Olig2 basic-helix-loop-helix transcription factor promotes oligodendrocyte specification in early neural progenitor cells (NPCs), including radial glial cells, in part by recruiting SWI/SNF chromatin remodeling complexes to the enhancers of genes involved in oligodendrocyte differentiation. How Olig2 expression is regulated during oligodendrogliogenesis is not clear. Here, we find that the Brg1 subunit of SWI/SNF complexes interacts with a proximal Olig2 promoter and represses Olig2 transcription in the mouse cortex at E14, when oligodendrocyte progenitors (OPCs) are not yet found in this location. Brg1 does not interact with the Olig2 promoter in the E14 ganglionic eminence, where NPCs differentiate into Olig2-positive OPCs. Consistent with these findings, Brg1-null NPCs demonstrate precocious expression of Olig2 in the cortex. However, these cells fail to differentiate into OPCs. We further find that Brg1 is necessary for neuroepithelial-to-radial glial cell transition, but not neuronal differentiation despite a reduction in expression of the pro-neural transcription factor Pax6. Collectively, these and earlier findings support a model whereby Brg1 promotes neurogenic radial glial progenitor cell specification but is dispensable for neuronal differentiation. Concurrently, Brg1 represses Olig2 expression and the specification of OPCs, but is required for OPC differentiation and oligodendrocyte maturation.

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

“…Olig2 can recruit Brg1, the ATPase subunit of switch/sucrose non-fermentable (SWI/SNF) chromatin-remodeling protein complexes, to gene enhancers that drive OL differentiation (15). Furthermore, we recently demonstrated that Brg1 regulates OPC specification and OL maturation by controlling expression of genes involved in early OL versus neuronal differentiation (16). In Caenorhabditis elegans, a homolog of FoxO3, FOXO interacts with the SWI/SNF complex to regulate life span (35).…”

Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

“…; Matsumoto et al . ). Brg1 ‐deficiency in embryonic RGPs inhibits the neurogenic to gliogenic switch but E16.5 cortical cultures lacking Brg1 are not impaired in astrocyte generation (Lessard et al .…”

“…During RGP lineage progression, BRG1 also controls OPC specification and oligodendrocyte formation by suppressing precocious Olig2 transcription (Matsumoto et al . ). Intriguingly, progenitor BAF displays mutually exclusive incorporation of either BAF170 or BAF155 at distinct developmental stages.…”

“…Progenitor BAF complex controls RGP proliferation and maintenance on different mechanistic levels: (i) by activating transcription of stem cell differentiation inhibitor Mash1 (Matsumoto et al . , ); (ii) by stimulating expression of Notch‐dependent proliferation‐promoting signals and (iii) by repressing SHH‐dependent differentiation‐promoting signals (Lessard et al . ).…”

“…BAF45a promotes progenitor cell proliferation and transition from neurogenic to gliogenic RGP cell fate in a BRG-dependent manner. Knockdown of progenitor BAF components in RGPs results in slow-down of the cell cycle and overall decrease of proliferating RGPs, thereby strongly reducing the numbers of IPs and upperlayer neurons (Lessard et al 2007;Matsumoto et al 2016). Brg1-deficiency in embryonic RGPs inhibits the neurogenic to gliogenic switch but E16.5 cortical cultures lacking Brg1 are not impaired in astrocyte generation (Lessard et al 2007).…”