Maternal immune activation in mice disrupts proteostasis in the fetal brain
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2021
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| Online Access: | https://hdl.handle.net/1721.1/134109 |
| _version_ | 1811071637428109312 |
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| author | Kalish, Brian T Kim, Eunha Finander, Benjamin Duffy, Erin E Kim, Hyunju Gilman, Casey K Yim, Yeong Shin Tong, Lilin Kaufman, Randal J Griffith, Eric C Choi, Gloria B Greenberg, Michael E Huh, Jun R |
| author_facet | Kalish, Brian T Kim, Eunha Finander, Benjamin Duffy, Erin E Kim, Hyunju Gilman, Casey K Yim, Yeong Shin Tong, Lilin Kaufman, Randal J Griffith, Eric C Choi, Gloria B Greenberg, Michael E Huh, Jun R |
| author_sort | Kalish, Brian T |
| collection | MIT |
| description | © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders. |
| first_indexed | 2024-09-23T08:54:20Z |
| format | Article |
| id | mit-1721.1/134109 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:54:20Z |
| publishDate | 2021 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1341092021-10-28T04:51:46Z Maternal immune activation in mice disrupts proteostasis in the fetal brain Kalish, Brian T Kim, Eunha Finander, Benjamin Duffy, Erin E Kim, Hyunju Gilman, Casey K Yim, Yeong Shin Tong, Lilin Kaufman, Randal J Griffith, Eric C Choi, Gloria B Greenberg, Michael E Huh, Jun R © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders. 2021-10-27T19:58:08Z 2021-10-27T19:58:08Z 2021 2021-07-07T16:28:59Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134109 en 10.1038/s41593-020-00762-9 Nature Neuroscience 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 | Kalish, Brian T Kim, Eunha Finander, Benjamin Duffy, Erin E Kim, Hyunju Gilman, Casey K Yim, Yeong Shin Tong, Lilin Kaufman, Randal J Griffith, Eric C Choi, Gloria B Greenberg, Michael E Huh, Jun R Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title | Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title_full | Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title_fullStr | Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title_full_unstemmed | Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title_short | Maternal immune activation in mice disrupts proteostasis in the fetal brain |
| title_sort | maternal immune activation in mice disrupts proteostasis in the fetal brain |
| url | https://hdl.handle.net/1721.1/134109 |
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