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

• DOI: 10.1016/j.neuron.2014.04.014
• Publication Date: 2014-05-08T15:48:57Z
• Authors: Kartik Pattabiraman; Olga Golonzhka; Susan Lindtner; Alex S. Nord; Leila Taher; Renee Hoch; Shanni N. Silberberg; Dongji Zhang; Bin Chen; HongKui Zeng; Len A. Pennacchio; Luis Puelles; Axel Visel; John L.R. Rubenstein
• Keywords: 0301 basic medicine; PAX6 Transcription Factor; Transcription, Genetic; *Gene Expression Regulation; Hippocampus; Transgenic; Mice; Cerebral Cortex/*embryology/*metabolism; *Enhancer Elements; Psychology; Paired Box Transcription Factors; Developmental; Cerebral Cortex; Pre-B-Cell Leukemia Transcription Factor 1; Gene Expression Regulation, Developmental; Hippocampus/embryology/metabolism; Enhancer Elements, Genetic; Neurological; Cognitive Sciences; *Transcription; Transcription; 570; Paired Box Transcription Factors/metabolism; Enhancer Elements; Eye Proteins/metabolism; 1.1 Normal biological development and functioning; Neuroscience(all); Mice, Transgenic; 03 medical and health sciences; Genetic; Underpinning research; Genetics; Homeodomain Proteins/metabolism; Animals; Humans; Transcription Factors/metabolism; Eye Proteins; Homeodomain Proteins; Neurology & Neurosurgery; Binding Sites; COUP Transcription Factor I; Biomedical and Clinical Sciences; Repressor Proteins/metabolism; Neurosciences; Repressor Proteins; Gene Expression Regulation; Biological psychology; COUP Transcription Factor I/metabolism; Transcription Factors

Elucidating 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. CreER(T2) 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.