TY - JOUR
T1 - One-Hit Wonders and 2-Hit Tubers
T2 - A Second-Hit to TSC2 Causes Tuber-Like Cells in Spheroids
AU - Goswami, Sonal
AU - Hsieh, Jenny
N1 - Publisher Copyright:
© The Author(s) 2019.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Genetically Engineered Human Cortical Spheroid Models of Tuberous Sclerosis Blair JD, Hockemeyer D, Bateup HS. Nat Med. 2018;24(10):1568-1578. doi:10.1038/s41591-018-0139-y. Epub 2018 Aug 20. PubMed PMID: 30127391; PubMed Central PMCID: PMC6261470. Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers—regions of dysmorphic, disorganized neurons, and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR–Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in 3-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
AB - Genetically Engineered Human Cortical Spheroid Models of Tuberous Sclerosis Blair JD, Hockemeyer D, Bateup HS. Nat Med. 2018;24(10):1568-1578. doi:10.1038/s41591-018-0139-y. Epub 2018 Aug 20. PubMed PMID: 30127391; PubMed Central PMCID: PMC6261470. Tuberous sclerosis complex (TSC) is a multisystem developmental disorder caused by mutations in the TSC1 or TSC2 genes, whose protein products are negative regulators of mechanistic target of rapamycin complex 1 signaling. Hallmark pathologies of TSC are cortical tubers—regions of dysmorphic, disorganized neurons, and glia in the cortex that are linked to epileptogenesis. To determine the developmental origin of tuber cells, we established human cellular models of TSC by CRISPR–Cas9-mediated gene editing of TSC1 or TSC2 in human pluripotent stem cells (hPSCs). Using heterozygous TSC2 hPSCs with a conditional mutation in the functional allele, we show that mosaic biallelic inactivation during neural progenitor expansion is necessary for the formation of dysplastic cells and increased glia production in 3-dimensional cortical spheroids. Our findings provide support for the second-hit model of cortical tuber formation and suggest that variable developmental timing of somatic mutations could contribute to the heterogeneity in the neurological presentation of TSC.
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U2 - 10.1177/1535759718822036
DO - 10.1177/1535759718822036
M3 - Comment/debate
C2 - 30838931
AN - SCOPUS:85061215496
SN - 1535-7597
VL - 19
SP - 49
EP - 50
JO - Epilepsy Currents
JF - Epilepsy Currents
IS - 1
ER -