Epigenetic Regulation by BAF Complexes Limits Neural Stem Cell Proliferation by Suppressing Wnt Signaling in Late Embryonic Development

摘要

class="head no_bottom_margin" id="sec1title">IntroductionDuring vertebrate cerebral cortex development, neural stem cells (NSCs) undergo two types of temporally regulated cell division modes to generate distinct neural cell types. During early corticogenesis in mice (embryonic day 8.5–12.5 [E8.5–E12.5]), NSCs, also called neuroepithelial cells (NEs), mainly divide symmetrically to proliferate and expand their population (, , , , ). At the onset of neurogenesis (E10.5), NEs differentiate into mature NSCs, also termed radial glial progenitors (RGs), which start to express astroglial markers (). This process coincides with the loss and appearance of tight and adherens junctional complexes respectively in the ventricular zone (VZ) (, ). Later, RGs primarily divide asymmetrically to produce an RG to maintain the proliferative pool, and either an excitatory neuron or a basal progenitor. Delayed RG differentiation from NEs causes aberrant neurogenesis (), yet factors that are required to suppress NE fate in late corticogenesis to ensure a balance between NSC proliferation and neuronal differentiation are unknown.The temporal relationship and intricate balance between proliferative symmetric and neurogenic asymmetric divisions in the VZ of the cortex is controlled by diverse signaling pathways. Among these, Wnt/β-catenin signaling has been extensively investigated for its role in proliferative symmetric division (). For example, elevation of Wnt signaling through overexpression of β-catenin massively enhanced cortical NSC proliferation (). Interestingly, a recent study revealed irreversibility of the progression from proliferative to neurogenic division modes, thus implicating a default program in NSCs for division-mode transition during corticogenesis (). As regulators of the spatiotemporal expression of developmental genes, epigenetic and chromatin regulatory mechanisms have been proposed to contribute to establishing the proliferative and differentiation competence of NSCs (, ).To investigate the possible involvement of chromatin-remodeling BAF (mSWI/SNF) complexes in this process, we applied a conditional deletion approach through double-knockout (dcKO) of the BAF155 and BAF170 subunits, which eliminate the entire BAF complex during late cortical neurogenesis in transgenic mice. In the absence of BAF complexes, transcriptional profiling and epigenetic analyses revealed an enrichment of downregulated RG (astroglial, adherens junctions)- and neuronal differentiation-related genes, with both gene groups showing increased H3K27me3 repressive marks. In contrast, upregulated genes with increased H3K4me2 active marks were predominantly involved in the regulation of NE cell fate (e.g., tight junction feature), proliferation, cell cycle, and Wnt signaling-related pathways. The results of this study suggest that BAF complexes exert genome-wide control on both active H3K4me2 and repressive H3K27me3 marks during late cortical development by directly interacting with the corresponding H3 demethylases and regulating their activity. Phenotypically, we found that deletion of BAF complexes during late cortical neurogenesis leads to dysgenesis of the upper cortical layers and the hippocampal formation. These perturbations were rescued by inhibition of Wnt/β-catenin signaling. Together, these observations provide insights into distinct epigenetic regulatory mechanisms mediated by chromatin-remodeling BAF complexes as a key factor that suppresses the proliferative competence of NSCs during late cortical development.