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Strictly co-isogenic C57BL/6J-Prnp−/−mice: A rigorous resource for prion science


Nuvolone, Mario; Hermann, Mario; Sorce, Silvia; Russo, Giancarlo; Tiberi, Cinzia; Schwarz, Petra; Minikel, Eric; Sanoudou, Despina; Pelczar, Pawel; Aguzzi, Adriano (2016). Strictly co-isogenic C57BL/6J-Prnp−/−mice: A rigorous resource for prion science. Journal of Experimental Medicine, 213(3):313-327.

Abstract

Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp−/− mice. However, all currently available Prnp−/− lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non–co-isogenic Prnp−/− mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease.

Abstract

Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp−/− mice. However, all currently available Prnp−/− lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non–co-isogenic Prnp−/− mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2016
Deposited On:21 Mar 2016 17:05
Last Modified:02 Feb 2018 09:54
Publisher:Rockefeller University Press
ISSN:0022-1007
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1084/jem.20151610
Official URL:http://jem.rupress.org/content/213/3/313.long
PubMed ID:26926995
Project Information:
  • : FunderH2020
  • : Grant ID670958
  • : Project TitlePRION2020 - Function and malfunction of the prion protein
  • : FunderFP7
  • : Grant ID250356
  • : Project TitlePRIONS - The prion protein in health and disease
  • : FunderFP7
  • : Grant ID278611
  • : Project TitleNEURINOX - NOX enzymes as mediators of inflammation-triggered neurodegeneration: modulating NOX enzymes as novel therapies

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