Identification of a core cross-regulatory neurogenic network regulated by the transcription factor Pax6 interacting with Brg1-containing SWI/SNF chromatin remodeling complex

The molecular mechanisms of neurogenic fate determination are of particular importance in light of the need to regenerate neurons. However the molecular logic of neurogenic fate determination is still ill understood, even though some key transcription factors have been implicated. Here we describe how one of these, the transcription factor Pax6, regulates adult neurogenesis by initiating a cross-regulatory network of 3 transcription factors executing neuronal fate and regulating genes required for neuronal differentiation. This network is initiated and driven to sufficiently high expression levels by the transcription factor Pax6 in close interaction with Brg1-containing SWI/SNF chromatin remodeling factors. Genetic deletion of either Pax6 or Brg1, the ATPase unit of the SWI/SNF complex, in neural stem cells of the adult mouse subependymal zone results in a fate conversion to distinct glial subtypes most pronounced when neuroblasts leave the neurogenic niche. Consistent with the phenocopy in vivo virtually all genes down-regulated by Brg1 deletion have Pax6-binding motifs. Amongst the few down-stream transcription factors are Sox11, Nfib and Brn4 that crossregulate each other and rescue neurogenesis also in direct reprogramming in the absence of Brg1 (or Pax6). Thus the function of Pax6-SWI/SNF is necessary and sufficient for neuronal fate maintenance and initiates a cross-regulatory effector network required for neuronal fate execution and maintenance to counteract glial differentiation in the adult brain. This identifies a novel role highly specific role of a chromatin-remodelling complex in stabilizing fate decisions in normal and forced neurogenesis. We performed gene expression microarray analysis on tissue derived from the SEZ or from the core region of the olfactory bulb from Brg1 cKO and control mice