Cortisol necessary for circadian rhythm of cell division

A new paper just came out today on PLoS-Biology: Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms. The paper is long and complicated, with many control experiments, etc, so I will just give you a very brief summary of the main finding.

One of the three major hypotheses for the origin of circadian clocks is the need to shield sensitive cellular processes - including cell division - from the effects of UV radiation by the sun, thus relegating it to night-time only:

The cyclic nature of energetic availability and cycles of potentially degrading effects of the sun's ultraviolet rays on particular pigmented enzymes, provided the selective environment. A cell with a timer can predict the changes and adjust its metabolic activities to minimize energetic and material loss. This cell will outcompete the other cells in the Archeozoic sea (Pittendrigh 1967).

Biological clocks in various organisms regulate timing of many different biochemical, physiological and behavioral events, but the circadian control of cell-cycle is really ubiqutous - it has been found in everything from bacteria to humans.

In many large organisms, the distinction between pacemakers and peripheral clocks is mainly in the ability of the pacemaker to synchronize itself to the outside environment and to send daily signals that act to synchronize all the peripheral clocks in all the cells in the body. The local clocks, then, regulate timing of local events.

In some organisms, peripheral clocks are also capable of direct sampling of the environment. Zebrafish is one such animal - its peripheral clocks (in every cell of the body) are photosensitive and entrainable directly by light-dark cycles. Only in constant light conditions does the brain pacemaker assume the role of the "conductor of the orchestra", synchronizing all the clocks in the body.

In vertebrates, it has been thought for a long time now that the central pacemaker (the SCN in the hypothalamus of the brain) uses, among else, cortisol as a signal for synchronizing the peripheral clocks. It times the release of corticotropins from the pituitary which in turn releases cortisol from the adrenal gland into the circulation at particular time of day. Various tissues are sensitive to cortisol and will use its surge as a timing/entraining signal.

In this paper, circadian rhythms of cell-division were shown to get attenuated in mutants that do not produce corticotropins (and thus do not produce cortisol). However, the clock genes still cycle normally in the periphery. Placing the fish in continous bath of cortisol agonist reinstates the circadian rhythms of cell division.

This suggests that cortisol is not a timing signal from the center to the periphery as the peripheral clocks keep cycling in its absence (and entrain directly - no need for any input from the eyes).

This also suggests that cortisol is neccessary for the coupling of the peripheral clock mechanism and its own output - the cell cycle. The presence of cortisol need not be rhythmic - it just needs to be there if the clock is to time the daily rhythms of cell division.