Targeted modification of the Per2 clock gene alters circadian function in mPer2.sup.luciferase mice

Modification of the Per2 clock gene in mPer2.sup.Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses...

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Bibliographic Details
Published in:PLoS computational biology 2021-05, Vol.17 (5)
Main Authors: Ralph, Ma, Shi, Shu-qun, Johnson, Carl H, Houdek, Pavel, Shrestha, Tenjin C, Crosby, Priya, O'Neill, John S, Sládek, Ma, Stinchcombe, Adam R, Sumová, Alena
Format: Article
Language:English
Subjects:
Analysis
Circadian rhythms
Luciferase
Methods
Molecular clock (Genetics)
Online Access:Get full text
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Summary:Modification of the Per2 clock gene in mPer2.sup.Luc reporter mice significantly alters circadian function. Behavioral period in constant dark is lengthened, and dissociates into two distinct components in constant light. Rhythms exhibit increased bimodality, enhanced phase resetting to light pulses, and altered entrainment to scheduled feeding. Mechanistic mathematical modelling predicts that enhanced protein interactions with the modified mPER2 C-terminus, combined with differential clock regulation among SCN subregions, can account for effects on circadian behavior via increased Per2 transcript and protein stability. PER2::LUC produces greater suppression of CLOCK:BMAL1 E-box activity than PER2. mPer2.sup.Luc carries a 72 bp deletion in exon 23 of Per2, and retains a neomycin resistance cassette that affects rhythm amplitude but not period. The results show that mPer2.sup.Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models.
ISSN:1553-734X
DOI:10.1371/journal.pcbi.1008987