Institute of Neuro and Behavioral Biology, Westfälische Wilhelms University, 48149 Münster, Germany.
Department of Physiology, Development, and Neuroscience, Cambridge University, Cambridge CB2 3EG, UK.
Curr Biol. 2020 Jul 6;30(13):2551-2563.e3. doi: 10.1016/j.cub.2020.04.067. Epub 2020 Jun 4.
The daily changes of light and dark exemplify a prominent cue for the synchronization of circadian clocks with the environment. The match between external and internal time is crucial for the fitness of organisms, and desynchronization has been linked to numerous physical and mental health problems. Organisms therefore developed complex and not fully understood mechanisms to synchronize their circadian clock to light. In mammals and in Drosophila, both the visual system and non-image-forming photoreceptors contribute to circadian clock resetting. In Drosophila, light-dependent degradation of the clock protein TIMELESS by the blue light photoreceptor Cryptochrome is considered the main mechanism for clock synchronization, although the visual system also contributes. To better understand the visual system contribution, we generated a genetic variant exhibiting extremely slow phototransduction kinetics, yet normal sensitivity. In this variant, the visual system is able to contribute its full share to circadian clock entrainment, both with regard to behavioral and molecular light synchronization. This function depends on an alternative phospholipase C-β enzyme, encoded by PLC21C, presumably playing a dedicated role in clock resetting. We show that this pathway requires the ubiquitin ligase CULLIN-3, possibly mediating CRY-independent degradation of TIMELESS during light:dark cycles. Our results suggest that the PLC21C-mediated contribution to circadian clock entrainment operates on a drastically slower timescale compared with fast, norpA-dependent visual phototransduction. Our findings are therefore consistent with the general idea that the visual system samples light over prolonged periods of time (h) in order to reliably synchronize their internal clocks with the external time.
光暗的日常变化为生物钟与环境同步提供了一个主要的线索。外部时间与内部时间的匹配对生物体的适应性至关重要，而生物钟的失同步与许多身心健康问题有关。因此，生物体发展出了复杂的、尚未完全理解的机制，将其生物钟与光同步。在哺乳动物和果蝇中，视觉系统和非成像光感受器都有助于生物钟的重置。在果蝇中，蓝光照感受器隐花色素介导的时钟蛋白 TIMELSS 的光依赖性降解被认为是时钟同步的主要机制，尽管视觉系统也有贡献。为了更好地理解视觉系统的贡献，我们产生了一个表现出极慢光转导动力学的遗传变异体，但仍保持正常的敏感性。在这个变体中，视觉系统能够在行为和分子水平上为生物钟的同步提供其全部的贡献。这种功能依赖于一种替代的 PLC21C 编码的磷脂酶 C-β 酶，可能在时钟重置中发挥专门作用。我们表明，这条途径需要泛素连接酶 CULLIN-3，可能介导了 CRY 非依赖性的 TIMELSS 在光暗周期中的降解。我们的结果表明，与快速的、依赖 norpA 的视觉光转导相比，PLC21C 介导的生物钟同步作用于一个明显较慢的时间尺度。因此，我们的发现与一般观点一致，即视觉系统在较长时间（小时）内对光进行采样，以便可靠地将其内部时钟与外部时间同步。
