TSC tunes progenitor balance and upper-layer neuron generation in neocortex

Nature. 2025 Dec 3. doi: 10.1038/s41586-025-09810-5. Online ahead of print.

ABSTRACT

The appropriate generation of upper-layer neurons is necessary to create the circuits that underlie complex brain functions. Radial progenitors divide asymmetrically to generate neurogenic intermediate progenitors (IPs; also known as intermediate precursors), and the symmetric proliferation of IPs rapidly expands the cortical neuronal population. The dynamic maintenance of balanced diversity of cortical progenitors and the resultant generation, placement and connectivity of appropriate numbers of different classes of neurons serve to guide the formation of a properly wired cerebral cortex^1-12. However, the molecular logic that instructs progenitor balance remains unclear. Here we show that members of the tuberous sclerosis complex (TSC)-proteins that are major regulators of cellular metabolism-function to sculpt radial progenitor-intermediate progenitor balance, radial unit organization and the resultant generation of upper-layer neurons. Developmental deletion of TSC proteins alters the radial progenitor and IP balance and changes radial unit composition, leading to increased upper-layer neuron generation and aberrant cortical connectivity. Human-specific modulation of TSC protein expression through human-gained enhancers affects progenitor balance and generation of upper-layer neurons. Evolutionary downregulation of TSC protein expression may therefore provide an effective route to radial unit sculpting and the expanded generation of upper-layer neurons necessary for higher-order brain functions in humans.

PMID:41339559 | DOI:10.1038/s41586-025-09810-5