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Differential manifestation of ocular phenotypes in TALEN-mediated p19arf knockout FVB/N and C57BL/6J mouse lines

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Abstract

Background

p19arf, primarily known as a tumor suppressor, has also been reported to play an essential role in normal development of mouse eyes. Consistently, lack of p19arf has been associated with ocular defects, but the mixed background of the knockout (KO) mouse strain used raised a concern on the accuracy of the phenotypes observed in association with the targeted gene due to genetic heterogeneity.

Object

We carried out a study to investigate into the effect of genetic background on the manifestation of p19arf KO associated phenotypes.

Methods

We characterized the phenotypes of novel p19arf KO mouse lines generated in FVB/N and C57BL/6J using a transcription activator-like effector nuclease (TALEN) system in comparison to the reported phenotypes of three other p19arf-deficient mouse lines generated using homologous recombination.

Results

Ninety-five percent of FVB/N-p19arf KO mice showed ocular opacity from week 4 after birth which worsened rapidly until week 6, while such abnormality was absent in C57BL/6J-p19arf KO mice up to the age of 26 weeks. Histopathological analysis revealed retrolental masses and dysplasia in the retinal layer in FVB/N-p19arf KO mice from week 4. Besides these, both strains developed normally from birth to week 26 without increased tumorigenesis except for a subcutaneous tumor found in a C57BL/6J-p19arf KO mouse.

Conclusion

Our findings demonstrated surprisingly variable manifestation of p19arf-linked phenotypes between FVB/N and C57BL/6J mice, and furthermore between our mouse lines and the established lines, indicating a critical impact of genetic background on functional study of genes using gene targeting strategies in mice.

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References

  • Cheong C, Sung YH, Lee J, Choi YS, Song J, Kee C, Lee H-W (2006) Role of INK4a locus in normal eye development and cataract genesis. Mech Ageing Dev 127:633–638

    Article  CAS  Google Scholar 

  • Dalke C et al (2004) Electroretinography as a screening method for mutations causing retinal dysfunction in mice. Investig Ophthalmol Vis Sci 45:601–609

    Article  Google Scholar 

  • Doetschman T (2009) Influence of genetic background on genetically engineered mouse phenotypes. Methods Mol Biol (Clifton, NJ) 530:423–433

    Article  CAS  Google Scholar 

  • Gaj T, Gersbach CA, Barbas CF III (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31:397–405

    Article  CAS  Google Scholar 

  • Hendrich HJ (2012) The laboratory mouse, 2nd edn. Elsevier, Italy

    Google Scholar 

  • Holzenberger M, Leneuve P, Hamard G, Ducos B, Perin L, Binoux M, Le Bouc Y (2000) A targeted partial invalidation of the insulin-like growth factor I receptor gene in mice causes a postnatal growth deficit. Endocrinology 141:2557–2566

    Article  CAS  Google Scholar 

  • Iqbal NS, Devitt CC, Sung CY, Skapek SX (2016) p19Arf limits primary vitreous cell proliferation driven by PDGF-B. Exp Eye Res 145:224–229

    Article  CAS  Google Scholar 

  • Kamijo T et al (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19 ARF. Cell 91:649–659

    Article  CAS  Google Scholar 

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci 95:8292–8297

    Article  CAS  Google Scholar 

  • Keane TM et al (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477:289–294

    Article  CAS  Google Scholar 

  • Kim J-I et al (2018) CRISPR/Cas9-mediated knockout of Rag-2 causes systemic lymphopenia with hypoplastic lymphoid organs in FVB mice. Lab Anim Res 34:166–175

    Article  Google Scholar 

  • Kim T-H, Son T, Le D, Yao X (2019) Longitudinal OCT and OCTA monitoring reveals accelerated regression of hyaloid vessels in retinal degeneration 10 (rd10) mice. Sci Rep 9:1–9

    Article  Google Scholar 

  • Lee JH et al (2020) The position of the target site for engineered nucleases improves the aberrant mRNA clearance in in vivo genome editing. Sci Rep 10:4173

    Article  CAS  Google Scholar 

  • Lilue J et al (2018) Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci. Nat Genet 50:1574–1583

    Article  CAS  Google Scholar 

  • Martin AC et al (2004) Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the arf tumor suppressor gene. Invest Ophthalmol Vis Sci 45:3387–3396

    Article  Google Scholar 

  • McKeller RN, Fowler JL, Cunningham JJ, Warner N, Smeyne RJ, Zindy F, Skapek SX (2002) The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development. Proc Natl Acad Sci 99:3848–3853

    Article  CAS  Google Scholar 

  • Montana CL, Kolesnikov AV, Shen SQ, Myers CA, Kefalov VJ, Corbo JC (2013) Reprogramming of adult rod photoreceptors prevents retinal degeneration. Proc Natl Acad Sci 110:1732–1737

    Article  CAS  Google Scholar 

  • NRC (2010) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, New York

    Google Scholar 

  • Park BM, Roh J-I, Lee J, Lee H-W (2018) Generation of knockout mouse models of cyclin-dependent kinase inhibitors by engineered nuclease-mediated genome editing. Lab Anim Res 34:264–269

    Article  Google Scholar 

  • Scacheri P et al (2001) Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice. Genesis 30:259–263

    Article  CAS  Google Scholar 

  • Serrano M, Lee H-W, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumor suppression and cell mortality. Cell 85:27–37

    Article  CAS  Google Scholar 

  • Tong C, Huang G, Ashton C, Li P, Ying Q-L (2011) Generating gene knockout rats by homologous recombination in embryonic stem cells. Nat Protoc 6:827

    Article  CAS  Google Scholar 

  • Valera A, Perales JC, Hatzoglou M, Bosch F (1994) Expression of the neomycin-resistance (neo) gene induces alterations in gene expression and metabolism. Hum Gene Ther 5:449–456

    Article  CAS  Google Scholar 

  • Weber JD et al (2000) p53-independent functions of the p19ARF tumor suppressor. Genes Dev 14:2358–2365

    Article  CAS  Google Scholar 

  • Wong AA, Brown RE (2006) Visual detection, pattern discrimination and visual acuity in 14 strains of mice. Genes Brain Behav 5:389–403

    Article  CAS  Google Scholar 

  • Yang J, Nan C, Ripps H, Shen W (2015) Destructive changes in the neuronal structure of the FVB/N mouse retina. PLoS One 10:e0129719

    Article  Google Scholar 

  • Yeo JH et al (2019) Development of a Pde6b gene knockout rat model for studies of degenerative retinal diseases. Investig Ophthalmol Vis Sci 60:1519–1526

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by a grant (14182MFDS978) from Ministry of Food and Drug Safety in 2015.

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Author notes

  1. Jin-Sung Park and Joo-Il Kim equally contributed to this work.

Authors and Affiliations

  1. Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea

    Jin-Sung Park, Joo-Il Kim, Hyun-Jin Lim, Soo-Kyung Ryu, Euna Kwon & Byeong-Cheol Kang

  2. Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Joo-Il Kim, Hyun-Jin Lim, Kang-Min Han & Byeong-Cheol Kang

  3. Department of Pathology, Dongguk University Ilsan Hospital, Goyang, Republic of Korea

    Kang-Min Han

  4. College of Medicine Severance Biomedical Science Institute, Yonsei University, Seoul, Republic of Korea

    Ki-Taek Nam

  5. Department of Biochemistry, Yonsei University, Seoul, Republic of Korea

    Han-Woong Lee

  6. Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, Republic of Korea

    Byeong-Cheol Kang

  7. Designed Animal Resource Center, Institute of GreenBio Science and Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, Republic of Korea

    Byeong-Cheol Kang

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  1. Jin-Sung Park
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Contributions

BCK, HWL and KT contributed to the study conception and design. Material preparation, data collection and analysis were performed by JSP, JIK, HJL, SR, EK and KMH. The first draft of the manuscript was written by JSP and JIK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Byeong-Cheol Kang.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All experiments were approved by the Institutional Animal Care and Use Committee (IACUC) in Seoul National University Hospital (Protocol number: 15-0031-C2A0(1)) and animals were maintained and used in accordance with Guide for the Care and Use of Laboratory Animals (NR 2010).

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Park, JS., Kim, JI., Lim, HJ. et al. Differential manifestation of ocular phenotypes in TALEN-mediated p19arf knockout FVB/N and C57BL/6J mouse lines. Genes Genom 42, 1023–1033 (2020). https://doi.org/10.1007/s13258-020-00959-z

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