Removal of a partial genomic duplication restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer
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Published:2023-11-14
Issue:1
Volume:21
Page:
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ISSN:1741-7007
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Container-title:BMC Biology
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language:en
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Short-container-title:BMC Biol
Author:
Bustos Fernando J.ORCID, Pandian Swarna, Haensgen Henny, Zhao Jian-Ping, Strouf Haley, Heidenreich Matthias, Swiech Lukasz, Deverman Benjamin E., Gradinaru Viviana, Zhang Feng, Constantine-Paton Martha
Abstract
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.
Funder
National Eye Institute McGovern Institute for Brain Research, Massachusetts Institute of Technology Pew Charitable Trusts Simons Center for the Social Brain, Massachusetts Institute of Technology ANID Universidad Andrés Bello
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Developmental Biology,Plant Science,General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Physiology,Ecology, Evolution, Behavior and Systematics,Structural Biology,Biotechnology
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