Cortical Development in a Human 3D Cellular Model of 22q11.2 Deletion Syndrome
Abstract/Contents
- Abstract
- 22q11.2 deletion syndrome (22q11DS) is a multi–system disorder characterized most frequently by a 3 Mb hemizygous deletion on chromosome 22. This disorder is the most common chromosomal microdeletion in humans and leads to significantly increased rates of neuropsychiatric disorders. Defects in corticogenesis are hypothesized to play a role in pathogenesis and have been investigated through MRI studies, postmortem studies, and mouse models, but have not been studied in human cells. Here, we investigated corticogenesis in 22q11DS using human cortical spheroids (hCS) differentiated from human induced pluripotent stems cells derived from 22q11DS and control subjects. We found that hCS differentiation showed no major differences in morphology and size between 22q11DS and control subjects. Transcriptional profiling of hCS using single–cell RNA–sequencing revealed similar cell composition and highly correlated gene expression. We found that genes within the 22q11.2 deletion exhibited, on average, a 50% reduction in 22q11DS patient derived hCS, including DGCR8, a miRNA processor. Differentially expressed genes, including 9 from the 22q11.2 locus, were enriched for transcriptional regulation, specifically of mRNA and RNA metabolic and catabolic pathways in gene ontology analysis. These findings indicate that early cortical differentiation may not be a significant contributor to developmental defects in 22q11DS, which makes hCS a reliable cellular model to study this disorder. Furthermore, we show that gene expression within the 22q11.2 locus, including DGCR8, is significantly downregulated and may play a role in dysregulating transcription in 22q11DS patient derived hCS.
Description
| Type of resource | text |
|---|---|
| Date created | May 15, 2020 |
Creators/Contributors
| Author | Schaepe, Julia Marie |
|---|---|
| Degree granting institution | Stanford University, Department of Psychiatry and Behavioral Sciences |
| Primary advisor | Pasca, Sergiu |
Subjects
| Subject | 22q11.2 Deletion Syndrome |
|---|---|
| Subject | human cortical spheroids |
| Subject | single-cell RNA-sequencing |
| Genre | Thesis |
Bibliographic information
| Related Publication | Khan, T.A., Revah, O., Gordon, A. et al. Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nat Med (2020). https://doi-org.stanford.idm.oclc.org/10.1038/s41591-020-1043-9 |
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| Related item | |
| Location | https://purl.stanford.edu/cj019mb3715 |
Access conditions
- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Preferred citation
- Preferred Citation
- Schaepe, Julia Marie. (2020). Cortical Development in a Human 3D Cellular Model of 22q11.2 Deletion Syndrome. Stanford Digital Repository. Available at: https://purl.stanford.edu/cj019mb3715
Collection
Undergraduate Theses, School of Engineering
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- Contact
- jmschaepe@gmail.com
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