Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice.
| Autor: | Ralph MR; Department of Psychology, University of Toronto, Toronto, Ontario, Canada., Shi SQ; Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America., Johnson CH; Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States of America., Houdek P; Laboratory of Biological Rhythms, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic., Shrestha TC; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada., Crosby P; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., O'Neill JS; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Sládek M; Laboratory of Biological Rhythms, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic., Stinchcombe AR; Department of Mathematics, University of Toronto, Toronto, Ontario, Canada., Sumová A; Laboratory of Biological Rhythms, Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic. |
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| Jazyk: | angličtina |
| Zdroj: | PLoS computational biology [PLoS Comput Biol] 2021 May 28; Vol. 17 (5), pp. e1008987. Date of Electronic Publication: 2021 May 28 (Print Publication: 2021). |
| DOI: | 10.1371/journal.pcbi.1008987 |
| Abstrakt: | Modification of the Per2 clock gene in mPer2Luc 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. mPer2Luc 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 mPer2Luc acts as a circadian clock mutation illustrating a need for detailed assessment of potential impacts of c-terminal tags in genetically modified animal models. Competing Interests: The authors have declared that no competing interests exist. |
| Databáze: | MEDLINE |
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