Shedding new light on entrainment of circadian clocks

By Mary Harrington

Scientists have been studying the entrainment of circadian rhythms as long as they have studied circadian clocks. Entrainment, the process by which internal rhythms are reset in order to match the period of the entraining cycle, has properties that are common across many life forms. Indeed, the theory of entrainment is one of the factors that unite the field of chronobiology, with principles that can apply to all life forms.

New discoveries from researchers working with mice are now revealing a surprising layer of circadian clocks that coexist with those driven by the brain circadian pacemaker in the suprachiasmatic nuclei (SCN). While it has been known for some time that intrinsically photosensitive retinal ganglion cells (ipRGCs) in the eye provide photic input to the SCN and mediate entrainment of SCN-generated circadian pacemaker signals, new research reveals that some circadian clocks in the mouse are directly photosensitive and that the body is indeed wrapped in a layer of such clocks.

Recent work by Ethan Buhr, Russell Van Gelder, and colleagues demonstrated that both retina and skin entrain their cellular circadian clocks by a direct pathway, a pathway that bypasses the ipRGCs and the SCN, and that uses an opsin called “neuropsin” or OPN5. Thus, the mammalian body is encased in a directly photosensitive circadian organ. This opsin is also located in cells in the preoptic hypothalamic region of the brain as well as in reproductive organs. Notably, the testes of both sexes also express multiple other photosensitive opsin molecules.

To better understand the functional significance of these novel opsins, Upton and colleagues (JBR April 2021) offer a detailed exploration of the evolutionary history of the mammalian opsin proteins. Interestingly, neuropsin (OPN5), the opsin present in skin, is more genetically constrained than any other opsin. In contrast, melanopsin (OPN4), the opsin member present in the ipRGCs, shows the most diversity within mammalian opsins. Although all mammalian lineages studied showed the presence of melanopsin, suggesting its importance across diverse niches, the diversity of the protein indicates evolution has shaped this molecule to serve animals living in widely ranging lighting habitats.

This new work expands our science in multiple ways. We expect chronobiologists will draw on the rich datasets and detailed literature review in Upton and colleagues’ paper to encompass consideration of mammals beyond a current favorite, the c57Bl6 mouse. Our concept of peripheral oscillators keeps getting stretched further and further. The JBR has hosted reviews describing peripheral clocks in various organs (the “Body Clocks” series), followed by a series of reviews about clocks in organisms that house other organisms (the “Embodied Clocks” series). Light sensitivity of circadian clocks beyond those getting direct input from the ipRGCs in the eye might be the newest advance, indicating biology has many more surprises for us.

Read the article

Article details

Evolutionary Constraint on Visual and Nonvisual Mammalian Opsins

Brian A. Upton, Nicolás M. Díaz, Shannon A. Gordon, Russell N. Van Gelder, Ethan D. Buhr, Richard A. Lang

First Published March 25, 2021 Research Article

DOI: 10.1177/0748730421999870

Journal of Biological Rhythms

About the author

Featured

Mary Harrington is the Editor-in-Chief of the Journal of Biological Rhythms. She is the Tippit Professor in Life Sciences at Smith College and currently chairs the Neuroscience Program. Her research is on mechanisms by which circadian rhythms adjust to environmental cues.