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

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

PROVIDER: PRJNA1253653 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2025-08-28 | GSE295166 | GEO

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

2025-08-27 | GSE298284 | GEO

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

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

| PRJNA1268879 | ENA

Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

Project description:Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

| PRJNA320885 | ENA

Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression

Project description:FoxP2 encodes a forkhead box transcription factor required for the development of neural circuits underlying language, vocalization, and motor-skill learning. Recent genetic studies have associated FOXP2 variation with neurodevelopmental disorders (NDDs), and within the cortex, it is coexpressed and interacts with other NDD-associated transcription factors. Cortical Foxp2 is required in mice for proper social interactions, but its role in other NDD-relevant behaviors is unknown. Here, we characterized such behaviors and their potential underlying cellular and molecular mechanisms in cortex-specific Foxp2 conditional knockout mice. These mice showed deficits in reversal learning without increased anxiety or hyperactivity. In contrast, they emitted normal vocalizations save for a decrease in loudness of neonatal calls. These behavioral phenotypes were accompanied by decreases in cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified neonatal D1R-expressing cell types in frontal cortex and found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits potentially relevant to NDDs.

2020-04-21 | GSE130653 | GEO

Staphylococcus aureus strain:Smith

Project description:Staphylococcus aureus strain:Smith Genome sequencing

| PRJNA392199 | ENA

Enterobase - NICD, A. Smith. Salmonella

Project description:Enterobase - NICD, A. Smith. Salmonella

| PRJEB39546 | ENA

Zingiber zerumbet cultivar:Smith

Project description:Zingiber zerumbet cultivar:Smith Raw sequence reads

| PRJNA277625 | ENA

Malus domestica breed:Granny smith

Project description:Malus domestica breed:Granny smith Assembly