Intrinsic DNA damage repair deficiency results in progressive microglia loss and replacement
Xiaoming Zhang1, Yang Heng1, Susanne M Kooistra1
1Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract:
The DNA excision repair protein Ercc1 is important for nucleotide excision, double strand DNA break, and interstrand DNA crosslink repair. In constitutive Ercc1-knockout mice, microglia display increased phagocytosis, proliferation and an enhanced responsiveness to lipopolysaccharide (LPS)-induced peripheral inflammation. However, the intrinsic effects of Ercc1-deficiency on microglia are unclear. In this study, Ercc1 was specifically deleted from Cx3cr1-expressing cells and changes in microglia morphology and immune responses at different times after deletion were determined. Microglia numbers were reduced with approximately 50% at 2-12 months after Ercc1 deletion. Larger and more ramified microglia were observed following Ercc1 deletion both in vivo and in organotypic hippocampal slice cultures. Ercc1-deficient microglia were progressively lost, and during this period, microglia proliferation was transiently increased. Ercc1-deficient microglia were gradually replaced by nondeficient microglia carrying a functional Ercc1 allele. In contrast to constitutive Ercc1-deficient mice, microglia-specific deletion of Ercc1 did not induce microglia activation or increase their responsiveness to a systemic LPS challenge. Gene expression analysis suggested that Ercc1 deletion in microglia induced a transient aging signature, which was different from a priming or disease-associated microglia gene expression profile.
Insights
Deleting the DNA repair protein Ercc1 from microglia did not cause activation. Instead, Ercc1 deficiency led to microglia loss and a transient aging signature, not inflammation.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- The DNA excision repair protein Ercc1 is crucial for DNA repair mechanisms.
- Constitutive Ercc1-knockout mice show altered microglia behavior, including increased phagocytosis and LPS responsiveness.
- The intrinsic impact of Ercc1 deficiency specifically within microglia remains largely unknown.
Purpose of the Study:
- To investigate the intrinsic effects of Ercc1 deficiency on microglia.
- To determine changes in microglia morphology and immune responses following specific Ercc1 deletion in Cx3cr1-expressing cells.
Main Methods:
- Specific deletion of Ercc1 in microglia using Cx3cr1-Cre mouse model.
- Analysis of microglia morphology, numbers, and proliferation in vivo and in organotypic hippocampal slice cultures.
- Assessment of microglia immune responses to lipopolysaccharide (LPS) challenge and gene expression analysis.
Main Results:
- Microglia numbers decreased by approximately 50% 2-12 months post-Ercc1 deletion.
- Ercc1-deficient microglia exhibited larger, more ramified morphology and transient proliferation.
- Microglia-specific Ercc1 deletion did not induce activation or heightened LPS responsiveness, unlike constitutive knockout models.
- Gene expression revealed a transient aging signature in deficient microglia, distinct from priming or disease-associated profiles.
Conclusions:
- Intrinsic Ercc1 deficiency in microglia leads to progressive loss and replacement by non-deficient cells.
- Ercc1 deficiency induces a unique transient aging signature in microglia, not activation or priming.
- These findings differentiate the intrinsic effects of Ercc1 loss in microglia from systemic or constitutive knockout scenarios.
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