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Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models

ABSTRACT: Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin 3-dimensional (3D) interactions in SMS hiPSC and 3D cortical organoids. Single-nucleus RNA-seq of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell cycle processes, and neuronal signalling. SMS cortical organoids had reduced growth, enlarged ventricles, and impaired cell cycle progression. In a complementary hiPSC-derived 2D cortical neuronal model, we found SMS cortical neurons had accelerated dendritic growth, followed by neuronal hyperexcitability that was associated with a reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295166 | GEO | 2025/08/28

REPOSITORIES: GEO

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Project description:Cerebral organoids â three-dimensional cultures of human cerebral tissue derived from pluripotent stem cells â have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex. Covariation network analysis using the fetal neocortex data reveals known and novel interactions among genes central to neural progenitor proliferation and neuronal differentiation. In the organoid, we detect diverse progenitors and differentiated cell types of neuronal and mesenchymal lineages, and identify cells that derived from regions resembling the fetal neocortex. We find that these organoid cortical cells use gene expression programs remarkably similar to those of the fetal tissue in order to organize into cerebral cortex-like regions. Our comparison of in vivo and in vitro cortical single cell transcriptomes illuminates the genetic features underlying human cortical development that can be studied in organoid cultures. 734 single-cell transcriptomes from human fetal neocortex or human cerebral organoids from multiple time points were analyzed in this study. All single cell samples were processed on the microfluidic Fluidigm C1 platform and contain 92 external RNA spike-ins. Fetal neocortex data were generated at 12 weeks post conception (chip 1: 81 cells; chip 2: 83 cells) and 13 weeks post conception (62 cells). Cerebral organoid data were generated from dissociated whole organoids derived from induced pluripotent stem cell line 409B2 (iPSC 409B2) at 33 days (40 cells), 35 days (68 cells), 37 days (71 cells), 41 days (74 cells), and 65 days (80 cells) after the start of embryoid body culture. Cerebral organoid data were also generated from microdissected cortical-like regions from H9 embryonic stem cell derived organoids at 53 days (region 1, 48 cells; region 2, 48 cells) or from iPSC 409B2 organoids at 58 days (region 3, 43 cells; region 4, 36 cells).

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Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models

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