Research in the recent years indicated that the immense neuronal diversity within mammalian cortical layers is generated during embryogenesis by pluripotent radial glial progenitors (RG) in the ventricular zone (VZ), through two modes of neurogenesis: a direct mode and an indirect mode, including generation of intermediate progenitors (IP) and outer radial glial progenitors (oRG) located in the subventricular zone (SVZ) and outer VZ (Figure 1). The second mode is assumed to account for the increase in cortical thickness and surface in primates during the evolution.
Figure 1: Different subtypes of cortical progenitors co-exist and are specified to generate distinct subtypes of cortical projection neurons and glia cells (LL: lower layer; UL: upper layer; MZ: mantle zone).
The neural identity is regulated by the transcriptional program and activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific transcriptional program that control neural development remains a challenge. We are interested in elucidating the role of two subunits (BAF155 and BAF170) of chromatin-remodeling BAF complex in brain development. Our previous study has identified the BAF170 as a intrinsic factor that controls cerebral cortical size. Mechanistically, BAF170 competes with BAF155 in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of Pax6 and the REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and modes of cortical neurogenesis (Figure 2 and Tuoc et al., 2013).
Figure 2: Hypothetical model demonstrating how exchange of BAF170 with BAF155 subunits in BAF170cKO and BAF170cOE cortices, and the coupling between Pax6, BAF, and REST complexes controls expression of genes involved in genesis of intermediate progenitors and the cortical development (Me: CpG methylation/H3K27Me3; Ac: K3K9Ac).
Future studies will focus to understand how chromatin regulation by BAF155/BAF170 and their binding proteins controls the neural development by using combination of genomic, proteomic approaches, advanced imaging and genetic manipulation.