| Autor: |
Ashley Tucewicz, Anthony Deo, Sean Simmons, Kwanho Kim, Kasper Lage, Giorgia Quadrato, Paola Arlotta, Xian Adiconis, Samantha Smith, Martina Pigoni, Bruna Paulsen, Kwanghun Chung, Aviv Regev, Kalliopi Tsafou, Joshua Z. Levin, Catherine Abbate, Alex Albanese, Silvia Velasco, Rafaela C. Sartore, Amanda J. Kedaigle, Ana Uzquiano |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.10.376509 |
| Popis: |
Genetic risk for autism spectrum disorder (ASD) has been associated with hundreds of genes spanning a wide range of biological functions. The phenotypic alterations in the human brain resulting from mutations in ASD risk genes remain unclear, and the level at which these alterations converge on shared disease pathology is poorly understood. Here, we leveraged reproducible organoid models of the human cerebral cortex to identify cell type-specific developmental abnormalities associated with haploinsufficiency in three ASD risk genes,SUV420H1(KMT5B),PTEN, andCHD8. We performed comprehensive single-cell RNA-sequencing (scRNA-seq) of over 400,000 cells, and proteomic analysis on individual organoids sampled at different developmental stages to investigate phenotypic convergence among these genes. We find that within a defined period of early cortical development, each of the three mutations demonstrates accelerated development of cortical neurons. Notably, they do so by affecting different neuronal populations: excitatory deep layer (SUV420H1) and callosal (PTEN) neurons, and inhibitory interneurons (CHD8). This work shows that haploinsufficiency in ASD risk genes converge on early developmental defects in the generation of neurons of the cortical microcircuit. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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