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J Exp Med. 2016 Mar 7;213(3):313-27. doi: 10.1084/jem.20151610. Epub 2016 Feb 29.

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

Author information

  • 1Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
  • 2Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
  • 3Functional Genomics Center Zurich (FGCZ), 8057 Zurich, Switzerland.
  • 4Prion Alliance, Cambridge, MA 02139 Broad Institute, Cambridge, MA 02142 Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114.
  • 5Fourth Department of Internal Medicine, Attikon Hospital, Medical School, University of Athens, 115 27 Athens, Greece.
  • 6Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
  • 7Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland adriano.aguzzi@usz.ch.

Abstract

Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrP(C)) remains enigmatic. A plethora of functions have been ascribed to PrP(C) 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 Prnp(ZH3/ZH3) mice failed to identify phenotypes previously described in non-co-isogenic Prnp(-/-) mice. However, aged Prnp(ZH3/ZH3) mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrP(C) in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrP(C) in physiology and disease.

PMID:
26926995
PMCID:
PMC4813672
DOI:
10.1084/jem.20151610
[PubMed - indexed for MEDLINE]
Free PMC Article
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