Transcriptional Regulation of Patterning of the Cerebral Cortex

The adult human cortex is divided into histologically and functionally distinct domains, which are specified early in development prior to neuronal differentiation. A handful of transcription factors (TFs) have been shown to be involved in pallial regionalization. Analysis of E11.5 expression data for 722 TFs has identified putative novel patterning TFs, which are expressed in gradients in pallium. From our analysis, we choose to study 28 TFs in more detail at E11.5. We investigated their expression in CoupTFI, Emx2 and Pax6 mouse mutants, TFs previously described to be involved in patterning.TFs with rostrocaudal gradients of expression showed similar changes in the Pax6 and CoupTf1 mutant. This finding is unexpected based on their opposing roles in patterning. We provide evidence that Pax6 and CoupTf1 work together in ventral cortical development. Furthermore, both TFs bind together on putative regulatory regions of genes involved in forebrain development. TFs that embryonically regulate pallial regionalization are expressed in gradients, raising the question of how discrete domains are generated. We provide evidence that small enhancer elements active in protodomains integrate broad transcriptional information. CreERT2 and GFP expression from 14 different enhancer elements in stable transgenic mice allowed us to define the first comprehensive regional fate map of the pallium. We explored transcriptional mechanisms that control the activity of the enhancers using informatics, in vivo occupancy by TFs that regulate cortical patterning (CoupTFI, Pax6 and Pbx1), and analysis of enhancer activity in Pax6 mutants. Overall, the results provide novel insights into how broadly expressed patterning TFs regulate the activity of small enhancer elements that drive gene expression in pallial protodomains that fate map to distinct cortical regions