Transcriptional Regulation of Enhancers Active in Protodomains of the Developing Cerebral Cortex

•Generated 14 different pallial enhancer CreERT2-IRES-GFP mouse lines•Defined pallial protodomains and cortical fates based on enhancer E11.5 activity•Defined enhancer regulation with ChIP-seq and in vitro and in vivo transcription assays•Enhancer protodomain expression integrates broad transcriptional information

SummaryElucidating the genetic control of cerebral cortical (pallial) development is essential for understanding function, evolution, and disorders of the brain. Transcription factors (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 a 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 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.