Amplification of human interneuron progenitors promotes brain tumors and neurological defects

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells overproliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.

Automated summary

The evolutionary development of the human brain involves the expansion of different brain regions. This study focuses on the specific developmental processes in humans that lead to malformations of cortical development, resulting in developmental delay and epilepsy in children. By creating a human cerebral organoid model for tuberous sclerosis complex (TSC), researchers identified a neural stem cell type called caudal late interneuron progenitor (CLIP) cells that overproliferate in TSC, leading to excessive interneurons, brain tumors, and cortical malformations. Inhibiting the epidermal growth factor receptor has potential therapeutic effects for TSC and related disorders. The discovery of CLIP cells highlights the vulnerability to disease in the extended generation of interneurons in the human brain, while also demonstrating the importance of analyzing malformations of cortical development in gaining insights into human-specific aspects of brain development.