TSC tunes progenitor balance and upper-layer neuron generation in neocortex
Summary
This Nature paper shows that the TSC complex (TSC1/TSC2 and partner TBC1D7), via mTOR signalling, is a key regulator of progenitor balance and the production of upper-layer neurons in the developing neocortex. Using mouse genetic models, mosaic analysis, electroporation, human neural progenitor studies and organoids, the authors demonstrate that loss or reduction of TSC components increases mTOR activity (pS6), expands progenitor proliferation, biases lineage output towards upper-layer neurons, enlarges cortical size and alters connectivity (for example increased corpus callosum width). Single-cell RNA-seq and epigenomic analyses link these changes to shifts in ASD-associated gene expression and to species-specific regulatory features of TSC genes.
Key Points
- Loss of TSC1/2 in neural progenitors elevates mTORC1 activity (marked by pS6) and expands the proliferative niche.
- TSC1/2 conditional knockout (cKO) increases generation and misplacement of upper-layer neurons, with larger cortical size and thicker corpus callosum.
- Mosaic and MADM analyses reveal altered laminar organisation, increased neurite branching and connectivity changes in TSC-deficient neurons.
- TBC1D7 (third TSC complex subunit) knockdown exacerbates cortical malformations in the TSC1/2-deficient background.
- scRNA-seq datasets (GEO GSE281619) show cell-type-specific transcriptional changes, including in genes linked to ASD/NDDs via the SFARI gene list.
- Epigenomic profiling indicates conserved sequence of TSC genes between mouse and human but human-specific chromatin signatures (H3K27me3/H3K27ac) that may modulate expression during corticogenesis.
- Candidate human-gained enhancers (HGEs) near TBC1D7 were identified, but CRISPRi perturbation in hNPCs did not robustly change TBC1D7 expression, suggesting complex regulation.
- Findings tie aberrant mTOR signalling during development to TSC neuropathology and provide mechanistic links to neurodevelopmental disorders such as autism.
Context and relevance
The study brings together genetics, single-cell transcriptomics and epigenomics to show how a core regulator of growth signalling (the TSC complex) sculpts neocortical development. It integrates prior work on mTOR in cortical progenitors and human-specific evolution of neocortex expansion, positioning TSC function as both a developmental regulator and a node for disease risk (tuberous sclerosis complex, cortical tubers, epilepsy and ASD-related changes). The availability of scRNA-seq and source data enables reanalysis and cross-comparison with other human development and disease datasets.
Why should I read this
Short version: if you care about how mTOR/TSC affects brain development, this paper is a proper deep dive. It explains why TSC mutations do more than cause growth — they alter which progenitors make which neurons, change cortical wiring and connect to autism-linked gene programmes. The authors also provide datasets and organoid/mouse evidence, so it’s useful whether you’re into basic cortical development, TSC neuropathology or translational approaches targeting mTOR.
Source
Article Date: 03 December 2025