Efficient in vivo manipulation of mouse genomic sequences at the zygote stage.
Open accessAbstract
We describe a transgenic mouse line carrying the cre transgene under the control of the adenovirus EIIa promoter that targets expression of the Cre recombinase to the early mouse embryo. To assess the ability of this recombinase to excise loxP-flanked DNA sequences at early stages of development, we bred EIIa-cre transgenic mice to two different mouse lines carrying loxP-flanked target sequences: (i) a strain with a single gene-targeted neomycin resistance gene flanked by 1oxP sites and (ii) a transgenic line carrying multiple transgene copies with internal loxP sites. Mating either of these loxP-carrying mouse lines to EIIa-cre mice resulted in first generation progeny in which the loxP-flanked sequences had been efficiently deleted from all tissues tested, including the germ cells. Interbreeding of these first generation progeny resulted in efficient germ-line transmission of the deletion to subsequent generations. These results demonstrate a method by which loxP-flanked DNA sequences can be efficiently deleted in the early mouse embryo. Potential applications of this approach are discussed, including reduction of multicopy transgene loci to produce single-copy transgenic lines and introduction of a variety of subtle mutations into the line.
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Tamoxifen-mediated CX3CR1CreER(Litt) expression increases Sholl intersections in pups (P7-P9).
“Tamoxifen-mediated Cre-recombinase expression under the promoter CX3CR1 (CX3CR1CreER(Litt)) has been shown to reduce IBA1+ microglia density in pups (P7-P9), while leading to increased IBA1+ microglia volume and Sholl intersections8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed Abstract (page not specified) describes Cre expression under the adenovirus EIIa promoter and deletion of loxP-flanked sequences in early mouse embryos. Searches for CX3CR1CreER, tamoxifen, microglia, and Sholl intersections found no passage addressing the claimed increase in Sholl intersections in P7–P9 pups. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe irregular microglial number and phenotype caused by early postnatal induction of CX3CR1CreER(Litt) normalize by adulthood.
“While the irregular microglial number and phenotype had normalized by adulthood”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed Abstract describes EIIa-cre-mediated deletion of loxP-flanked sequences in early mouse embryos, not microglia. Searches for microglial normalization and CX3CR1CreER(Litt) found no passage addressing either; the available copy links to the full text but does not provide the potentially decisive body text. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTamoxifen-mediated CX3CR1CreER(Litt) expression increases IBA1+ microglia volume in pups (P7-P9).
“Tamoxifen-mediated Cre-recombinase expression under the promoter CX3CR1 (CX3CR1CreER(Litt)) has been shown to reduce IBA1+ microglia density in pups (P7-P9), while leading to increased IBA1+ microglia volume and Sholl intersections8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed Abstract describes EIIa-promoter Cre activity in early mouse embryos, not tamoxifen-mediated CX3CR1CreER activity or microglia in P7–P9 pups. Searches for CX3CR1CreER, IBA1, microglia volume, and Sholl intersections found no relevant passage. Our copy links to a PDF but does not include its body text, so the claim cannot be verified from it. (LLM, conf=0.75)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER(Litt) causes DNA damage in microglia during the early postnatal period.
“The authors found a lower microglial density, an altered phenotype, upregulation of their phagocytic function, and DNA damage in the Cre+ microglia of the developing brain.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not supplied) describes EIIa-Cre-mediated deletion of loxP-flanked sequences in early mouse embryos, not early postnatal CX3CR1CreER(Litt) induction. Searches for CX3CR1CreER(Litt), microglia, DNA damage, density, and phagocytic function found no relevant passage in our copy; the article body is represented only by a PDF link. (LLM, conf=0.75)
Experimental — accuracy not yet measuredTamoxifen-mediated CX3CR1CreER(Litt) expression decreases the number of proliferating microglia in the early postnatal period.
“It has been shown that tamoxifen-mediated Cre-recombinase expression (CX3CR1CreER(Litt)) decreases the number of proliferating microglia, thereby suggesting decreased proliferation of early postnatal microglia, as well as induces DNA damage in the early postnatal period8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not provided) describes EIIa-promoter-driven Cre recombinase activity in early mouse embryos. Searches for CX3CR1CreER(Litt), tamoxifen, microglial proliferation, and DNA damage found no passage addressing the claimed effect; the indexed copy shows an abstract and references but not the article body. (LLM, conf=0.73)
Experimental — accuracy not yet measured
Early postnatal induction of CX3CR1CreER(Litt) increases anxiety-like behavior in adulthood.
“these unintended and non-specific effects of CX3CR1-driven Cre-recombinase expression in early postnatal microglia caused the animals to display increased anxiety-like behavior in adulthood8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed Abstract (no page given) describes EIIa-driven Cre recombination in early mouse embryos, not CX3CR1-driven Cre expression in postnatal microglia. Searches for CX3CR1CreER, microglia, and adult anxiety-like behavior found no passage addressing the claimed behavioral effect; the available copy shows no article-body text beyond a PDF link. (LLM, conf=0.74)
Experimental — accuracy not yet measuredEarly postnatal tamoxifen-mediated induction of CX3CR1CreER(Litt) enhances microglial synaptic engulfment in pups.
“early postnatal tamoxifen-mediated induction of CX3CR1CreER(Litt) has been shown to enhance microglial synaptic engulfment in pups8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The available Abstract describes EIIa-Cre-mediated deletion of loxP-flanked sequences in early mouse embryos, not postnatal CX3CR1CreER induction or microglial synaptic engulfment. Searches for CX3CR1CreER, tamoxifen, and microglial engulfment found no relevant passage. Our copy displays a PDF link rather than the article body, so the claim cannot be assessed from the available text. (LLM, conf=0.74)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER(Litt) alters microglial phenotype.
“The authors found a lower microglial density, an altered phenotype, upregulation of their phagocytic function, and DNA damage in the Cre+ microglia of the developing brain.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not specified in our copy) describes EIIa-cre-mediated deletion of loxP-flanked sequences in early mouse embryos. Searches for CX3CR1CreER(Litt), microglial density, phagocytic function, and DNA damage found no passage addressing the claimed postnatal microglial effects; the available copy does not provide the article’s body text. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER(Litt) upregulates microglial phagocytic function.
“The authors found a lower microglial density, an altered phenotype, upregulation of their phagocytic function, and DNA damage in the Cre+ microglia of the developing brain.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not provided) describes EIIa-Cre-mediated deletion of loxP-flanked sequences in early mouse embryos. Searches for CX3CR1CreER, microglial phagocytosis, microglial density, and DNA damage found no passage addressing the claimed effects of early postnatal induction. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe adverse effects of CX3CR1-driven Cre-recombinase expression are limited to Cre-recombinase expression under the CX3CR1 promoter and to its induction during early postnatal ages.
“Interestingly, these effects were shown to be limited only to Cre-recombinase expression under the CX3CR1 promoter and to its induction during early postnatal ages8.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The available copy describes Cre expression under the adenovirus EIIa promoter in early mouse embryos (Abstract; no page given). Searches for CX3CR1, adverse effects, and early postnatal induction found no passage addressing whether such effects are limited to that promoter or age. (LLM, conf=0.77)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER(Litt) reduces microglial density in the developing brain.
“The authors found a lower microglial density, an altered phenotype, upregulation of their phagocytic function, and DNA damage in the Cre+ microglia of the developing brain.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not provided) describes EIIa-cre-mediated deletion of DNA sequences in early mouse embryos, not CX3CR1CreER induction. Searches for microglial density, phagocytic function, and DNA damage found no passage in our copy addressing the attributed findings. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER leads to increased anxiety-like behavior in adulthood.
“This finding contrasts with the key finding from Sahasrabuddhe et al.8, which shows that early postnatal induction of CX3CR1CreER leads to IFN-1 signaling activation, increased developmental synaptic pruning in the somatosensory cortex, and increased anxiety-like behavior in adulthood.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (page not specified in our copy) describes EIIa-cre–mediated deletion of DNA sequences in early mouse embryos. Searches for CX3CR1CreER, postnatal induction, anxiety-like behavior, IFN-1 signaling, and synaptic pruning found no passage addressing the claimed adult behavioral effect. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER leads to increased developmental synaptic pruning in the somatosensory cortex.
“This finding contrasts with the key finding from Sahasrabuddhe et al.8, which shows that early postnatal induction of CX3CR1CreER leads to IFN-1 signaling activation, increased developmental synaptic pruning in the somatosensory cortex, and increased anxiety-like behavior in adulthood.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed Abstract describes EIIa-cre-mediated deletion of loxP-flanked sequences in early mouse embryos, not early postnatal CX3CR1CreER induction. Searches for CX3CR1CreER, synaptic pruning, and somatosensory cortex found no passage addressing the attributed finding; the available copy shows an abstract and references rather than the article body. (LLM, conf=0.74)
Experimental — accuracy not yet measuredEarly postnatal induction of CX3CR1CreER leads to IFN-1 signaling activation.
“This finding contrasts with the key finding from Sahasrabuddhe et al.8, which shows that early postnatal induction of CX3CR1CreER leads to IFN-1 signaling activation, increased developmental synaptic pruning in the somatosensory cortex, and increased anxiety-like behavior in adulthood.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract describes EIIa-cre–mediated deletion of loxP-flanked sequences in early mouse embryos. Searches for CX3CR1CreER, early postnatal induction, and type I interferon signaling found no passage addressing the claimed effect. The copy also does not name a work by Sahasrabuddhe, so it cannot establish an actual source for the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe trigger for IFN-1 signaling in the inducible Cre model is DNA damage.
“which was the trigger for the IFN-1 signaling in the inducible Cre model8”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The available Abstract describes EIIa-Cre-mediated deletion of loxP-flanked sequences in early mouse embryos, but does not discuss IFN-1 signaling or DNA damage. Searches for those terms returned only the abstract and references; the indexed copy does not include the article's substantive full-text sections, so it cannot settle the claimed trigger. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe phosphorylated-gamma-H2AX antibody used to detect DNA damage here was the same as used in the previous study.
“The phosphorylated-gamma-H2AX antibody used to detect DNA damage here was the same as used in the previous study8”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The available Abstract describes Cre-loxP deletion in early mouse embryos, not DNA-damage detection. Searches for phosphorylated γ-H2AX, H2AX antibody, and immunostaining found no relevant passage; the available copy does not establish whether the same antibody was used. (LLM, conf=0.72)
Experimental — accuracy not yet measuredOur findings and previous studies recognize the drawbacks of adverse and off-target effects, especially when employing this tool to study naturally reactive cells, such as microglia.
“Nevertheless, our findings and previous studies8,9 recognize the drawbacks of adverse and off-target effects, especially when employing this tool to study naturally reactive cells, such as microglia.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The indexed copy’s Abstract describes efficient Cre-mediated deletion in early mouse embryos, while its remaining passages are references and links to figures. Searches for adverse or off-target effects, Cre toxicity, and microglia found no passage addressing those drawbacks; the article body is not present in the indexed text. (LLM, conf=0.73)
Experimental — accuracy not yet measuredReduced time spent in the center zone is considered to be a marker of anxiety-like behavior.
“Reduced time spent in the center zone is considered to be a marker of anxiety-like behavior8,21.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The Abstract (p. 5860) describes Cre-mediated deletion of DNA sequences in mouse embryos, not a behavioral measure. Searches for center-zone time, open-field behavior, and anxiety found no passage in our copy addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredReduced time spent exploring the open arms is used as a marker for anxiety-like behavior.
“Reduced time spent exploring the open arms is used as a marker for anxiety-like behavior8,22.”
From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [8]
The available text describes Cre-mediated manipulation of mouse genomic sequences, not behavioral testing. Searches for open-arm exploration and the elevated plus maze found no passage linking reduced open-arm time to anxiety-like behavior; the available copy contains an abstract and references but not the article body. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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“The cross to CreElla created a partial recombinant allele such that the NeoPGK cassette is excised while the loxP sites flanking exon-2 remain intact (Figure 4, Table 2; Holzenberger et al. 2000; Lakso et al. 1996; Walisser et al. 2005).”
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- Authors
- Lakso, M., Pichel, J. G., Gorman, J. R., Sauer, B., Okamoto, Y., Lee, E., Alt, F. W., & Westphal, H.
- Affiliations
- National Institutes of Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-06-11
- Volume
- 93
- Issue
- 12
- Pages
- 5860-5865
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC39152
- OpenAlex
- W2058172887
- Cited by
- 1,125
- References
- 1
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 31 · 2023: 39 · 2022: 28 · 2021: 29 · 2020: 45 · 2019: 34 · 2018: 43 · 2017: 45 · 2016: 49 · 2015: 40 · 2014: 49 · 2013: 41 · 2012: 53
- FWCI
- 11.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (A.I. 20047, A.I.31541)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- Cre recombinase, loxP sites, zygote, early mouse embryo, germline transmission, gene targeting, neomycin resistance gene, conditional gene deletion
- MeSH terms
- Animals, DNA, DNA Nucleotidyltransferases, Eye Neoplasms, Female, Lens, Crystalline, Male, Mice, Transgenic, Viral Proteins, Zygote, Genome, Transgenes, Integrases, Mice
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