Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The tauopathy-like phenotype observed in the rTg4510 mouse line, in which human tauP301L expression specifically within the forebrain can be temporally controlled, has largely been attributed to high overexpression of mutant human tau in the forebrain region. Unexpectedly, we found that in a different mouse line with a targeted-insertion of the same transgene driven by the same tetracycline-TransActivator (tTA) allele, but with even higher overexpression of tauP301L than rTg4510, atrophy and tau histopathology are delayed, and a different behavioral profile is observed. This suggests that it is not overexpression of mutant human tau alone that contributes to the phenotype in rTg4510 mice. Furthermore we show that the tauopathy-like phenotype seen in rTg4510 requires a ~70-copy tau-transgene insertion in a 244 kb deletion in Fgf14, a ~7-copy tTA-transgene insertion in a 508 kb deletion that disrupts another five genes, in addition to high transgene overexpression. We propose that these additional effects need to be accounted for in any studies using rTg4510.

Original languageEnglish (US)
Article number2479
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank the University of Minnesota Genomics Center (UMGC), Daryl Gohl in particular, for advising us in experimental design and for conducting the whole-genome sequencing experiments. We acknowledge Kevin Silverstein at the Minnesota Supercomputing Institute (MSI), whose suggestions for computational approaches aided our identification of the insertion location of the transgene sequence. In addition, MSI’s computational research infrastructure was used for this task. We thank Kailee Leinonen, Elizabeth Steuer, and Eric Huang for their assistance with mouse breeding, genotyping, and behavioral tests. Cytogenetic analyses were performed in the Cytogenomics Shared Resource at the University of Minnesota with support from the comprehensive Masonic Cancer Center NIH Grant #P30 CA077598. This research received histology assistance from the University of Minnesota’s Biorepository and Laboratory Services program and was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. Partial support for EF was provided by the Office of the Director, National Institutes of Health (NIH) under award number K01-OD019912. This work was supported in part by a Zenith Award from the Alzheimer’s Association to M.K. and K.A.

Publisher Copyright:
© 2019, The Author(s).

Fingerprint Dive into the research topics of 'Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice'. Together they form a unique fingerprint.

Cite this