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

• DOI: 10.1016/j.stemcr.2018.04.014
• Publication Date: 2018-05-17T14:54:02Z
• Authors: Huong Nguyen; Cemil Kerimoglu; Mehdi Pirouz; Linh Pham; Kamila A. Kiszka; Godwin Sokpor; M. Sadman Sakib; Joachim Rosenbusch; Ulrike Teichmann; Rho H. Seong; Anastassia Stoykova; Andre Fischer; Jochen F. Staiger; Tran Tuoc
• Keywords: 0301 basic medicine; Chromosomal Proteins, Non-Histone; Neurogenesis; Embryonic Development; Fluorescent Antibody Technique; metabolism [Hippocampus]; genetics [Chromosomal Proteins, Non-Histone]; metabolism [Neural Stem Cells]; Hippocampus; Article; Epigenesis, Genetic; Gene Knockout Techniques; Mice; 03 medical and health sciences; genetics [Ribonucleoproteins]; Neural Stem Cells; Animals; ddc:610; cytology [Neural Stem Cells]; Wnt Signaling Pathway; Cell Proliferation; Neurons; Gene Expression Regulation, Developmental; Cell Differentiation; genetics [Embryonic Development]; Chromatin Assembly and Disassembly; Ribonucleoproteins; metabolism [Neurons]; cytology [Neurons]; embryology [Hippocampus]; metabolism [Chromosomal Proteins, Non-Histone]; metabolism [Ribonucleoproteins]; Protein Binding

During 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.