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CX3CR1-BAC-Cre的组成型表达在小胶质细胞中引入的脱靶效应最小。

Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia.

作者信息

Mroue-Ruiz Fadya H, Desai Bhoomi, Garvin Madison, Shehu Jonila, Kamau Faith, Kar Urjoshi, Bolton Jessica L

机构信息

Neuroscience Institute, Georgia State University.

出版信息

bioRxiv. 2024 Nov 3:2024.11.01.621625. doi: 10.1101/2024.11.01.621625.

DOI:10.1101/2024.11.01.621625
PMID:39554070
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11566009/
Abstract

CX3CR1-Cre mouse lines have produced important advancements in our understanding of microglial biology. Recent studies have demonstrated the adverse effects of tamoxifen-induced CX3CR1-Cre expression during development, which include changes in microglial density, phenotype, and DNA damage, as well as anxiety-like behavior. However, the unintended effects of constitutive CX3CR1-BAC-Cre expression remain unexplored. Here, we characterized the effects of CX3CR1-BAC-Cre expression on microglia in CX3CR1-BAC-Cre+/- and CX3CR1-BAC-Cre-/- male and female littermates during early postnatal development and adulthood in multiple brain regions. Additionally, we performed anxiety-like behavior tests to assess changes caused by Cre expression. We found that CX3CR1-BAC-Cre expression causes subtle region- and sex-specific changes in microglial density, volume, and morphology during development, but these changes normalized by adulthood in all brain regions except the hippocampus. No behavioral effects were found. Our findings suggest that the constitutive-Cre model might be less detrimental than the inducible model, and highlight the need for proper controls.

摘要

CX3CR1-Cre小鼠品系在我们对小胶质细胞生物学的理解方面取得了重要进展。最近的研究表明，他莫昔芬诱导的CX3CR1-Cre在发育过程中的表达具有不良影响，包括小胶质细胞密度、表型和DNA损伤的变化，以及类似焦虑的行为。然而，组成型CX3CR1-BAC-Cre表达的意外影响仍未得到探索。在这里，我们表征了CX3CR1-BAC-Cre表达对CX3CR1-BAC-Cre+/-和CX3CR1-BAC-Cre-/-雄性和雌性同窝幼崽在出生后早期发育和成年期多个脑区小胶质细胞的影响。此外，我们进行了类似焦虑行为测试，以评估Cre表达引起的变化。我们发现，CX3CR1-BAC-Cre表达在发育过程中会导致小胶质细胞密度、体积和形态出现细微的区域和性别特异性变化，但除海马体外，所有脑区的这些变化在成年期都会恢复正常。未发现行为影响。我们 的研究结果表明，组成型Cre模型可能比诱导型模型的有害性更小，并强调了适当对照的必要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/803192c70426/nihpp-2024.11.01.621625v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/100729e10047/nihpp-2024.11.01.621625v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/65816443f501/nihpp-2024.11.01.621625v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/6c3171310976/nihpp-2024.11.01.621625v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/803192c70426/nihpp-2024.11.01.621625v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/100729e10047/nihpp-2024.11.01.621625v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/65816443f501/nihpp-2024.11.01.621625v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/6c3171310976/nihpp-2024.11.01.621625v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/391b/11566009/803192c70426/nihpp-2024.11.01.621625v1-f0004.jpg

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本文引用的文献

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Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice.慢性社会挫败应激后，小胶质细胞依赖性过度突触修剪导致小鼠皮质连接不足和行为异常。
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Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain.Cx3Cr1-Cre 诱导导致早期产后大脑中 DNA 损伤引起的小胶质细胞激活和 IFN-1 信号转导。
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