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.
Highlights
The tauopathy-like phenotype observed in the rTg4510 mouse line, in which human tauP301L expression within the forebrain can be temporally controlled, has largely been attributed to high overexpression of mutant human tau in the forebrain region
We find that mice from this targeted-insertion line overexpress even more tauP301L than rTg4510, these mice exhibit significantly delayed overt atrophy and tau histopathology and an abnormal age-related flight response
Using whole-genome sequence analyses, we find that the transgene insertion/deletion (TgINDEL) mutation linked to the confounding effects in rTg4510 is an approximately 70-copy tau-transgene insertion in a ~250 kb deletion of the first exons and promoter regions of fbroblast growth factor 14 (Fgf14)
Summary
The tauopathy-like phenotype observed in the rTg4510 mouse line, in which human tauP301L expression within the forebrain can be temporally controlled, has largely been attributed to high overexpression of mutant human tau in the forebrain region. 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. The rapid onset and severity of neuron loss in this model was surprising when first reported given that earlier mouse models incorporating similar human microtubuleassociated protein tau (MAPT) transgenes with the pathogenic P301L mutation do not develop overt atrophy[3,4] Unlike these other tauP301L overexpression models, rTg4510 uses a responder-driver system to activate transgene expression in forebrain neurons. We find that, in the absence of the Fgf[14] tauTgINDEL, matching the high level of transgene overexpression in rTg4510 appears to be necessary to cause premature (≤7 months) tau histopathology, late-stage (>12 months) overt atrophy, and behavior abnormalities
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