title: Strictly co-isogenic C57BL/6J-Prnp-/- mice: A rigorous resource for prion science.
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.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Nuvolone
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Hermann
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sorce
authors.affiliation: Functional Genomics Center Zurich (FGCZ), 8057 Zurich, Switzerland.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Russo
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tiberi
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.affiliation: Prion Alliance, Cambridge, MA 02139 Broad Institute, Cambridge, MA 02142 Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Eric
authors.initials: E
authors.lastname: Minikel
authors.affiliation: Fourth Department of Internal Medicine, Attikon Hospital, Medical School, University of Athens, 115 27 Athens, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Sanoudou
authors.affiliation: Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Pelczar
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland adriano.aguzzi@usz.ch.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D001483:Base Sequence; D033481:Chromosomes, Mammalian; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics; D010587:Phagocytosis; D010641:Phenotype; D011129:Polyradiculoneuropathy / Q000473:pathology; D011328:Prions / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015534:Trans-Activators / Q000235:genetics
chemical_list: D011328:Prions; D015534:Trans-Activators; D012313:RNA; D004720:Endonucleases