Autism genes converge on asynchronous development of shared neuron classes
Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8....
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2023
|
| Online Access: | https://hdl.handle.net/1721.1/147065 |
| _version_ | 1811072938257940480 |
|---|---|
| author | Paulsen, Bruna Velasco, Silvia Kedaigle, Amanda J Pigoni, Martina Quadrato, Giorgia Deo, Anthony J Adiconis, Xian Uzquiano, Ana Sartore, Rafaela Yang, Sung Min Simmons, Sean K Symvoulidis, Panagiotis Kim, Kwanho Tsafou, Kalliopi Podury, Archana Abbate, Catherine Tucewicz, Ashley Smith, Samantha N Albanese, Alexandre Barrett, Lindy Sanjana, Neville E Shi, Xi Chung, Kwanghun Lage, Kasper Boyden, Edward S Regev, Aviv Levin, Joshua Z Arlotta, Paola |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Paulsen, Bruna Velasco, Silvia Kedaigle, Amanda J Pigoni, Martina Quadrato, Giorgia Deo, Anthony J Adiconis, Xian Uzquiano, Ana Sartore, Rafaela Yang, Sung Min Simmons, Sean K Symvoulidis, Panagiotis Kim, Kwanho Tsafou, Kalliopi Podury, Archana Abbate, Catherine Tucewicz, Ashley Smith, Samantha N Albanese, Alexandre Barrett, Lindy Sanjana, Neville E Shi, Xi Chung, Kwanghun Lage, Kasper Boyden, Edward S Regev, Aviv Levin, Joshua Z Arlotta, Paola |
| author_sort | Paulsen, Bruna |
| collection | MIT |
| description | Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology. |
| first_indexed | 2024-09-23T09:22:58Z |
| format | Article |
| id | mit-1721.1/147065 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:22:58Z |
| publishDate | 2023 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1470652023-01-12T03:42:01Z Autism genes converge on asynchronous development of shared neuron classes Paulsen, Bruna Velasco, Silvia Kedaigle, Amanda J Pigoni, Martina Quadrato, Giorgia Deo, Anthony J Adiconis, Xian Uzquiano, Ana Sartore, Rafaela Yang, Sung Min Simmons, Sean K Symvoulidis, Panagiotis Kim, Kwanho Tsafou, Kalliopi Podury, Archana Abbate, Catherine Tucewicz, Ashley Smith, Samantha N Albanese, Alexandre Barrett, Lindy Sanjana, Neville E Shi, Xi Chung, Kwanghun Lage, Kasper Boyden, Edward S Regev, Aviv Levin, Joshua Z Arlotta, Paola Massachusetts Institute of Technology. Department of Biology Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology. 2023-01-11T17:49:20Z 2023-01-11T17:49:20Z 2022 2023-01-11T17:41:18Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147065 Paulsen, Bruna, Velasco, Silvia, Kedaigle, Amanda J, Pigoni, Martina, Quadrato, Giorgia et al. 2022. "Autism genes converge on asynchronous development of shared neuron classes." Nature, 602 (7896). en 10.1038/S41586-021-04358-6 Nature Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Paulsen, Bruna Velasco, Silvia Kedaigle, Amanda J Pigoni, Martina Quadrato, Giorgia Deo, Anthony J Adiconis, Xian Uzquiano, Ana Sartore, Rafaela Yang, Sung Min Simmons, Sean K Symvoulidis, Panagiotis Kim, Kwanho Tsafou, Kalliopi Podury, Archana Abbate, Catherine Tucewicz, Ashley Smith, Samantha N Albanese, Alexandre Barrett, Lindy Sanjana, Neville E Shi, Xi Chung, Kwanghun Lage, Kasper Boyden, Edward S Regev, Aviv Levin, Joshua Z Arlotta, Paola Autism genes converge on asynchronous development of shared neuron classes |
| title | Autism genes converge on asynchronous development of shared neuron classes |
| title_full | Autism genes converge on asynchronous development of shared neuron classes |
| title_fullStr | Autism genes converge on asynchronous development of shared neuron classes |
| title_full_unstemmed | Autism genes converge on asynchronous development of shared neuron classes |
| title_short | Autism genes converge on asynchronous development of shared neuron classes |
| title_sort | autism genes converge on asynchronous development of shared neuron classes |
| url | https://hdl.handle.net/1721.1/147065 |
| work_keys_str_mv | AT paulsenbruna autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT velascosilvia autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT kedaigleamandaj autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT pigonimartina autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT quadratogiorgia autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT deoanthonyj autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT adiconisxian autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT uzquianoana autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT sartorerafaela autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT yangsungmin autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT simmonsseank autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT symvoulidispanagiotis autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT kimkwanho autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT tsafoukalliopi autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT poduryarchana autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT abbatecatherine autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT tucewiczashley autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT smithsamanthan autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT albanesealexandre autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT barrettlindy autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT sanjananevillee autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT shixi autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT chungkwanghun autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT lagekasper autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT boydenedwards autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT regevaviv autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT levinjoshuaz autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses AT arlottapaola autismgenesconvergeonasynchronousdevelopmentofsharedneuronclasses |