Enhancer Activity Defines Progenitor Cell Identity in the Developing Subpallium of the Mouse
During brain development, the subpallium is responsible for generating a wide range of cell types with different molecular, electrophysiological, and morphological properties. These cells integrate into the mature forebrain to form circuits with complex behavioral output. How this diversity of cells is specified during development is essential to understanding the evolution, function and disorders of the brain. This work used enhancers with subpallial activity to study genetic mechanisms of cell type specification in the subpallium. We generated 10 transgenic mouse lines each harboring a human enhancer driving GFP and CreERT2. Using these novel tools we showed how enhancer activity delineates the subpallium into spatial and temporal progenitor domains that give rise to different mature cell types including unique populations of cortical interneurons and amygdala neurons. We identified transcription factors necessary for enhancer activity through luciferase assays, mutant crosses, and transcription factor ChIP-seq experiments. Using machine learning we built a predictive model of enhancer activity and identified transcription factors important for subregional and laminar activity of enhancers. These findings contribute to our current understanding of cell type specification and point to enhancers as key regulators of cell fate.