Redondance génétique et synchronisation cellulaire dans les horloges circadiennes

Abstract

L’horloge circadienne des mammifères, localisée dans les noyaux suprachiasmatiques, assure la coordination temporelle d’une multitude d’oscillateurs au sein de l’organisme. Cela permet de répartir les fonctions cellulaires et physiologiques à différents temps de la journée. Les gènes de l’horloge constituent la base moléculaire du système. Cet article discute les mécanismes moléculaires de l’horloge à la lumière de nouvelles données concernant l’un de ces gènes : Clock. Replacées dans un contexte plus large, ces données montrent que la redondance génétique et les mécanismes de couplage cellulaire permettent de construire différents types d’horloges possédant divers degrés de plasticité et de robustesse.

A network of feedback loops constitutes the basis for circadian timing in mammals. Complex transcriptional, post-transcriptional and post-translational events are also involved in the ticking of circadian clocks, allowing them to run autonomously with their characteristic, near-24h period. Central to the molecular mechanism is the CLOCK/BMAL1 heterodimer of transcription factors. Recent data using Clock knock-out mice however suggest that CLOCK may not be as mandatory as initially suggested from data gathered in the Clock mutant mouse model. Indeed, it appears that the Clock homolog Npas2 is able to functionally compensate for Clock genetic ablation. Furthermore, real-time imaging techniques using different clock genes knock-out lines established on a PER2 ::Luc knock-in background now demonstrate that persistent rhythmicity in the suprachiasmatic nuclei likely arises as a consequence of combined genetic redundancy and strong intercellular coupling, the latter characteristic being likely weakened in peripheral tissues such as liver or lung. The present review aims at summarizing current knowledge of the molecular basis of circadian clocks and possible differences between central and peripheral clocks in light of recent findings in Clock knock-out mice.