Modelling translational regulation of PER and its effects over the circadian molecular clock

CONDAT, C.A.; NIETO, P.S.

CABA

Congreso; nd Congress of the Federation of Latin-American and Caribbean Societies for Neuroscience (FALAN); 2016

At the single cell level the circadian clock is based on a set of clock genes and proteins expressed in a circadian fashion as consequence of their mutual interaction based on interconnected feedback loops. Translation of some clock proteins, like PER in Drosophila or PER1, 2, 3 in mammals, is affected by regulatory proteins and/or microRNAs, highlighting the critical role of translational regulation in the circadian clock dynamics. In flies for instance, the TYF-ATX2-PABP complex critically activates PER translation in central pacemaker neurons but is apparently dispensable for PER translation in peripheral cells. In this work we hypothesize that changes in the kinetics of PER synthesis derive from translational regulation, which in turn depends on regulatory proteins and/or microRNAs. We used a mathematical model of the core molecular clock for describing different kinetic mechanisms of PER synthesis and studying their effects on the clock dynamics. Our results show that the kinetics of PER translation ultimately affect the circadian period, oscillation amplitude and time lag between mRNA and protein expression. We interpreted different kinetic laws in terms of translational regulation by microRNAs and/or modulatory proteins as TYF. We can predict the time delay between Per mRNA and protein expression in different translational contexts and the clock dynamics for tyf mutants.