Every cell every gene all at once: Systems genetic approaches toward corticogenesis

The development of the cerebral cortex is a stepwise process that involves numerous cell types and signaling pathways to achieve the functional assembly of neural circuits. Our understanding of this process is primarily rooted in findings from studying transgenic knockout models, which reveal coordinated molecular actions, particularly transcription factor cascades critical for cell type acquisition and maintenance in a context-dependent manner. Further resolving their cell type specificity necessitates the use of high-throughput, high-content methodologies. Over the past decade, the emerging single-cell genomics and in vivo CRISPR tools have provided new approaches to study neurodevelopment with elevated scale and resolution. In this review, we discussed efforts to study mouse cortical cell fate determination using single-cell genomics methods. Additionally, we explored recent studies combining programmable gene editing with single-cell phenotypic assays to investigate the function of transcription factors in perinatal cortical development, delineating cell-type specific, functional cytoarchitecture of the developing brain.