Neural Progenitors Promote Malformations in Tuberous Sclerosis Complex

Caused by loss-of-function mutations in one of two tumor suppressor genes, TSC1 or TSC2, tuberous sclerosis complex (TSC) is a rare genetic disease characterized by neuropsychiatric disorders and malformations in the brain, among other features. Patients display focal dysplastic regions in the cortex, known as cortical tubers, and form subependymal nodules (SEN), which can develop into benign tumors called subependymal giant cell astrocytomas (SEGA). Given that efforts to study TSC in genetic murine models have shown inconsistencies with patient data, Eichmüller and colleagues generated a human cerebral organoid model, hypothesizing that TSC disease initiation involves processes specific to human brain development. To mirror TSC pathology, cerebral organoids were generated from TSC2⁺/⁻ patient-derived induced pluripotent stem cells and cultured in high- or low-nutrient medium to favor formation of SEN/SEGA-like or cortical tuber–like lesions, respectively. Single-cell RNA-sequencing analysis of SEN/SEGA-like lesions revealed that these tumors were mostly composed of interneurons and interneuron progenitors. Notably, genotypic analysis of these tumors found that, although some tumors became homozygous for a TSC2 allele through copy-neutral loss of heterozygosity (cnLOH), as seen in human patients, a cnLOH event or additional mutation at the TSC1 or TSC2 locus was not required for tumor initiation. To identify whether tumors and tubers shared a common cell of origin, both types of organoids were analyzed as TSC phenotypes began to emerge, suggesting that the predominant cells in TSC organoids originated from the caudal ganglion eminence (CGE), based on marker expression. Integration of this data with analysis of cell types involved in the developmental trajectory of the human fetal brain highlighted a population of CGE progenitors that emerge during late midgestation, termed caudal late interneuron progenitors (CLIP). CLIP cells were shown to initiate both TSC tumors and cortical tubers and to rely on epidermal growth factor signaling. In summary, this work highlights the expansion of a neurodevelopmental cell type that underlies the pathology and progression of TSC.

Eichmüller OL, Corsini NS, Vertesy A, Morassut I, Scholl T, Gruber VE, et al. Amplification of human interneuron progenitors promotes brain tumors and neurological defects. Science 2022;375:eabf5546.

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