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Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish.

Authors
  • Swanson, Laura C1, 2
  • Trujillo, Edna A3, 4
  • Thiede, Gene H1
  • Katzenberger, Rebeccah J1
  • Shishkova, Evgenia4, 5
  • Coon, Joshua J3, 4, 5, 6
  • Ganetzky, Barry7
  • Wassarman, David A8
  • 1 Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 2 Medical Scientist Training Program, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 3 Department of Chemistry, College of Letters & Science, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 4 National Center for Quantitative Biology of Complex Systems, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 5 Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 6 Morgridge Institute for Research, Madison, Wisconsin 53706.
  • 7 Department of Genetics, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706.
  • 8 Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53706 [email protected]
Type
Published Article
Journal
Genetics
Publisher
The Genetics Society of America
Publication Date
Dec 01, 2020
Volume
216
Issue
4
Pages
1117–1136
Identifiers
DOI: 10.1534/genetics.120.303776
PMID: 33109529
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by nuclear factor-κB (NF-κB) transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-κB factors Dif and Relish (Rel), respectively. Here, we found by mass spectrometry that Rel protein level increased in fly heads at 4-8 hr after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Rel del , by CRISPR/Cas9 editing. When heterozygous but not homozygous, the Rel del mutation reduced mortality at 24 hr after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygosity for Rel del on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of Rel del on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Rel del , and Rel del /Rel del flies at 4 hr following TBI. Only a few genes changed expression more than twofold in +/Rel del flies relative to +/+ and Rel del /Rel del flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes. Copyright © 2020 by the Genetics Society of America.

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