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

Huong Nguyen,Cemil Kerimoglu,Godwin Sokpor,Tran Tuoc,Kamila A Kiszka,Joachim Rosenbusch,Rho H Seong,Anastassia Stoykova,Jochen F Staiger,Linh Pham,Ulrike Teichmann,Andre Fischer,Mehdi Pirouz,M Sadman Sakib

doi:10.1016/j.stemcr.2018.04.014

Abstract

SummaryDuring early cortical development, neural stem cells (NSCs) divide symmetrically to expand the progenitor pool, whereas, in later stages, NSCs divide asymmetrically to self-renew and produce other cell types. The timely switch from such proliferative to differentiative division critically determines progenitor and neuron numbers. However, the mechanisms that limit proliferative division in late cortical development are not fully understood. Here, we show that the BAF (mSWI/SNF) complexes restrict proliferative competence and promote neuronal differentiation in late corticogenesis. Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling. Notably, the deletion of BAF complexes increased proliferation of neuroepithelial cell-like NSCs, impaired neuronal differentiation, and exerted a Wnt-dependent effect on neocortical and hippocampal development. Thus, these results demonstrate that BAF complexes act as both activators and repressors to control global epigenetic and gene expression programs in late corticogenesis.

Highlights

During vertebrate cerebral cortex development, neural stem cells (NSCs) undergo two types of temporally regulated cell division modes to generate distinct neural cell types
Loss of BAF Complexes Causes a Genome-wide Increase in the Level of Both Active and Repressive Epigenetic Marks at Distinct Loci in the Developing Pallium during Late Neurogenesis We previously reported that BAF complexes potentiate the activity of two main H3K27 demethylases, JMJD3 and UTX
SATB2+ and CUX1+ neurons (Figures S4A–S4D), as observed in dcKO pallium with enhanced level of H3K27me3. These findings suggest that deletion of BAF complexes in late NSCs leads to H3K27me3-linked silencing of neuronal differentiation genes and results in diminished late cortical and hippocampal neurogenesis

Summary

Introduction

During vertebrate cerebral cortex development, neural stem cells (NSCs) undergo two types of temporally regulated cell division modes to generate distinct neural cell types. At the onset of neurogenesis (E10.5), NEs differentiate into mature NSCs, termed radial glial progenitors (RGs), which start to express astroglial markers (Hartfuss et al, 2001). This process coincides with the loss and appearance of tight and adherens junctional complexes respectively in the ventricular zone (VZ) (Aaku-Saraste et al, 1996; Sahara and O’Leary, 2009). Delayed RG differentiation from NEs causes aberrant neurogenesis (Sahara and O’Leary, 2009), yet factors that are required to suppress NE fate in late corticogenesis to ensure a balance between NSC proliferation and neuronal differentiation are unknown

Results

Discussion

Conclusion