| Autor: |
Kostic M; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Raymond JJ; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Freyre CAC; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Henry B; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Tumkaya T; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States.; Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Khlghatyan J; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Dvornik J; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Li J; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Hsiao JS; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Cheon SH; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Chung J; Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Sun Y; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Dolmetsch RE; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Worringer KA; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States., Ihry RJ; Neuroscience, Novartis Institutes for BioMedical Research, Cambridge 02139, Massachusetts, United States. |
| Abstrakt: |
Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases. |
