RT Journal Article
SR Electronic
T1 Cerebral organoid model reveals excessive proliferation of human caudal late interneuron progenitors in Tuberous Sclerosis Complex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.27.967802
DO 10.1101/2020.02.27.967802
A1 Oliver L. Eichmüller
A1 Nina S. Corsini
A1 Ábel Vértesy
A1 Theresa Scholl
A1 Victoria-Elisabeth Gruber
A1 Angela M. Peer
A1 Julia Chu
A1 Maria Novatchkova
A1 Mercedes F. Paredes
A1 Martha Feucht
A1 Jürgen A. Knoblich
YR 2020
UL http://biorxiv.org/content/early/2020/02/27/2020.02.27.967802.abstract
AB Although the intricate and prolonged development of the human brain critically distinguishes it from other mammals1, our current understanding of neurodevelopmental diseases is largely based on work using animal models. Recent studies revealed that neural progenitors in the human brain are profoundly different from those found in rodent animal models2–5. Moreover, post-mortem studies revealed extensive migration of interneurons into the late-gestational and post-natal human prefrontal cortex that does not occur in rodents6. Here, we use cerebral organoids to show that overproduction of mid-gestational human interneurons causes Tuberous Sclerosis Complex (TSC), a severe neuro-developmental disorder associated with mutations in TSC1 and TSC2. We identify a previously uncharacterized population of caudal late interneuron progenitors, the CLIP-cells. In organoids derived from patients carrying heterozygous TSC2 mutations, dysregulation of mTOR signaling leads to CLIP-cell over-proliferation and formation of cortical tubers and subependymal tumors. Surprisingly, second-hit events resulting from copy-neutral loss-of-heterozygosity (cnLOH) are not causative for but occur during the progression of tumor lesions. Instead, EGFR signaling is required for tumor proliferation, opening up a promising approach to treat TSC lesions. Our study demonstrates that the analysis of developmental disorders in organoid models can lead to fundamental insights into human brain development and neuropsychiatric disorders.