Tuberous Sclerosis Complex Regulates Progenitor Balance and Upper Layer Neuronal Generation During the Development and Evolution of the Cerebral Cortex

Radial progenitors serve to coordinate the generation and placement of appropriate numbers and types of neurons in the developing cerebral cortex. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs) and the symmetric proliferation of IPs rapidly expands cortical neuronal population. The temporal maintenance of a balanced diversity of cortical progenitors and the resultant generation, placement, and connectivity of appropriate numbers of different classes of neurons serve as a blueprint to guide the formation of a properly wired cerebral cortex. Here, we show that Tuberous Sclerosis Complex proteins function to facilitate radial progenitor/intermediate progenitor balance and the generation of upper-layer neurons. Regulation of TSC expression levels during human brain evolution may lead to the expanded generation of upper-layer neurons necessary for higher-order brain functions in humans. 10x single-cell RNA-seq of P0 cerebral cortical neurons from control and TSC1/2 cKO mice, 3-4 biological replicates each. One animal in the control group of scRNAseq experiments was excluded based on poor RNA quality. TSC1_TSC2_control replicates 1, 3, and 4 were subsequently renamed to TSC1_TSC2_control_Rep1, TSC1_TSC2_control_Rep2, and TSC1_TSC2_control_Rep3, respectively, for publication.