Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
Oliver L EichmüllerNina S CorsiniAbel VertesyIlaria MorassutTheresa SchollVictoria-Elisabeth GruberAngela M PeerJulia ChuMaria NovatchkovaJohannes A HainfellnerMercedes F ParedesMartha FeuchtJuergen A KnoblichPublished in: Science (New York, N.Y.) (2022)
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 over-proliferate, 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.
Keyphrases
- induced apoptosis
- endothelial cells
- epidermal growth factor receptor
- cell cycle arrest
- induced pluripotent stem cells
- endoplasmic reticulum stress
- pluripotent stem cells
- cerebral ischemia
- young adults
- cell death
- white matter
- genome wide
- oxidative stress
- multiple sclerosis
- climate change
- tyrosine kinase
- signaling pathway
- physical activity
- cell proliferation
- body mass index
- resting state
- subarachnoid hemorrhage
- dna methylation
- pi k akt
- weight gain
- functional connectivity
- risk factors
- endoscopic submucosal dissection
- human health
- cerebral blood flow
- temporal lobe epilepsy