Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Brain / embryology
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Brain / pathology*
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology*
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Carcinogenesis
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Cell Lineage
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Cell Proliferation
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Disease Progression
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism
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Gene Expression Profiling
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Humans
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Induced Pluripotent Stem Cells
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Interneurons / cytology*
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Interneurons / physiology
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Loss of Heterozygosity
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Neural Stem Cells / cytology
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Neural Stem Cells / physiology*
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Organoids
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RNA-Seq
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TOR Serine-Threonine Kinases / metabolism
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Tuberous Sclerosis / drug therapy
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Tuberous Sclerosis / genetics*
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Tuberous Sclerosis / metabolism
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Tuberous Sclerosis / pathology*
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Tuberous Sclerosis Complex 1 Protein / genetics
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Tuberous Sclerosis Complex 1 Protein / metabolism
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Tuberous Sclerosis Complex 2 Protein / genetics
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Tuberous Sclerosis Complex 2 Protein / metabolism
Substances
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TSC1 protein, human
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TSC2 protein, human
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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MTOR protein, human
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EGFR protein, human
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ErbB Receptors
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TOR Serine-Threonine Kinases