Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer
Abstract Background Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BioMed Central
2023
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| Online Access: | https://hdl.handle.net/1721.1/153013 |
| _version_ | 1826200796416442368 |
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| author | Bustos, Fernando J. Pandian, Swarna Haensgen, Henny Zhao, Jian-Ping Strouf, Haley Heidenreich, Matthias Swiech, Lukasz Deverman, Benjamin E. Gradinaru, Viviana Zhang, Feng Constantine-Paton, Martha |
| author2 | McGovern Institute for Brain Research at MIT |
| author_facet | McGovern Institute for Brain Research at MIT Bustos, Fernando J. Pandian, Swarna Haensgen, Henny Zhao, Jian-Ping Strouf, Haley Heidenreich, Matthias Swiech, Lukasz Deverman, Benjamin E. Gradinaru, Viviana Zhang, Feng Constantine-Paton, Martha |
| author_sort | Bustos, Fernando J. |
| collection | MIT |
| description | Abstract
Background
Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies.
Results
Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD.
Conclusions
Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases. |
| first_indexed | 2024-09-23T11:41:55Z |
| format | Article |
| id | mit-1721.1/153013 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:41:55Z |
| publishDate | 2023 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1530132024-01-23T19:46:41Z Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer Bustos, Fernando J. Pandian, Swarna Haensgen, Henny Zhao, Jian-Ping Strouf, Haley Heidenreich, Matthias Swiech, Lukasz Deverman, Benjamin E. Gradinaru, Viviana Zhang, Feng Constantine-Paton, Martha McGovern Institute for Brain Research at MIT Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Abstract Background Copy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Results Using the ASD and anxiety mouse model Flailer, which contains a partial genomic duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700 bp genomic region in vitro and in vivo. Importantly, DN-CRISPRs have not been used to remove genomic regions using sgRNA with an offset greater than 300 bp. We found that editing the flailer gene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene editing. Delivery of DN-CRISPRs in vivo shows that local delivery to the ventral hippocampus can rescue some of the mutant behaviors, while intracerebroventricular delivery, completely recovers the Flailer animal phenotype associated to anxiety and ASD. Conclusions Our results demonstrate the potential of DN-CRISPR to efficiently remove larger genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases. 2023-11-21T13:51:12Z 2023-11-21T13:51:12Z 2023-11-14 2023-11-19T04:54:20Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/153013 BMC Biology. 2023 Nov 14;21(1):232 PUBLISHER_CC PUBLISHER_CC en https://doi.org/10.1186/s12915-023-01714-y Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ BioMed Central Ltd., part of Springer Nature application/pdf BioMed Central |
| spellingShingle | Bustos, Fernando J. Pandian, Swarna Haensgen, Henny Zhao, Jian-Ping Strouf, Haley Heidenreich, Matthias Swiech, Lukasz Deverman, Benjamin E. Gradinaru, Viviana Zhang, Feng Constantine-Paton, Martha Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title | Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title_full | Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title_fullStr | Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title_full_unstemmed | Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title_short | Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer |
| title_sort | removal of a partial genomic duplication restores synaptic transmission and behavior in the myosinva mutant mouse flailer |
| url | https://hdl.handle.net/1721.1/153013 |
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