Category Archives: Circadian Clock

Prolactin acts on stem cells – understanding circannual behaviour?

Prolactin is the hormone that regulates mammary gland development in man. However, in animals it is the main functional regulator to transmit the physiological reaction to the seasons, its expression is dependent on the day length, which is measured in calendar cells close to the hypophyseal stalk, and which activate prolactin expression when the day time increases, and vice versa.

How prolactin could in turn influence different functions such as increase in mating behaviour, coat colour changes or molt, the song in birds, e.g., has been an open question. A minireview in Molecular Endocrinology by Sackmann-Sala and colleagues from the  Institut Necker in Paris, France, may shed light on this issue. They show that in humans, mice, and rats prolactin acts on stem cells in a tissue specific way. The tissues in question are reproductive tissues, but apart from that also special regions of the brain, and peripheral tissues.

If each of the functions as mediated from the progeny of individual stem cells, then a stimulating role of the pleiotropic prolactin activities is easily understood. The paper does not address this question, but it opens a new way of thinking.

For this reason, do not miss it if you are concerned with circannual regulation. 

Melatonin required to fall asleep – in fish

Reading about circadian rhymth in flies I happened to see the Neuron paper by Gandhi et al. about melatonins role in fish. Melatonin – the hormone of the pineal gland – has been shown already to be active in the determination of seasons, its amount produced during the night being measure in so-called calendar cells in the vicinity of the hyphyseal stalk. Now the authors in Pasadena show that melatonin is necessary to fall asleep: zebrafish without the critical enzyme of melatonin systhesis: aanat2 (arylalkylamine N-acetyltransferase 2) take much longer to fall asleep and do not sleep as long as control animals.

Whether the data do apply to men and mammals is open. This is, however, a nice piece of work. It does not explain while I can start sleeping extensively during day time when there is not any melatonin in my circulation.

When timing matters

When you are an endocrinologist you know that hormones are released into the circulation in pulses and that melatonin is only produced in the dark, that glucocortoids concentrations in the blood are high during the night and low during the day, that many hormones have their rhythm. Every hormone has its time, as the prophet sayed.

However, what has not been known until now is that to the same extend more than 40 % of all genes are expressed in a circadian (day long) rhythm.  Zhang and colleagues measured in the mouse ( and the might be the only shortcoming of the study ) the gene expression with arrays to determine many gene simultaneously in every hour of the day and night. They found 43 % of all genes expressed in a circadian rhythm. They also determined noncoding RNAs  and found 1000 of them cycling.

There are consequences for medicine and therapy: The targets of the top most drugs are expressed all in (specific) rhythms: When a drug like aspirin for example is taken at the wrong time, it would be gone before the target is fully expressed. The scale of this problem seems tremendous. Any pharmaceutical company has to do its home work again. But on the other hand, therapy might become more reliable which would be a large improvement.

The circadian rhythm in the 12 organs analysed are quite different. It might take some time to get used to the thinking that genes in question are not stable during the day but change the level of expression. It will be interesting to follow the aftermath of that paper. The paper is open access and therefore free to everybody.

A must.


Clock gene necessary for implantation

Endocrinologists are aware of the circadian clock since it determines the release of many hormone likewise cortisol in a daily rhythm. There are other rhythmic hormone releases not dependent on the circadian clock, for example the prolactin release in a circannual fashion, or faster pulses for hormones of the pituitary with one to three hours pulse lengths.

In short, the circadion clock is found in the supraoptic nucleus of the hypothalamus and concists of the RNAs and proteins Per, BMAL, Clock, and cryptochrome(s). These are generated and inactivated in a way that autonomously repeats about every 24 hours. It can also adjust to a light-dark cycle.

What is new in a paper by Liu et al. from the Bradfield labaratory at the Univ. of Wisconsin in PNAS is that steroidogenesis — the synthesis of steroids –is coupled to the clock protein BMAL-1. They show that female mice which fail to express the BMAL protein in steroidogenic cells are not capable to implant an fertilized egg into the uterus and fail to generate progeny. When they transplant one normal uterus into these animals  by exchanging one defective with the normal one, these mice will again produce offspring. The defect can, in addition, be rescued by soluble progesterone which shows that progesterone is a determining factor in nidation/implantation.

These experiments are nicely done. The conclusion, however, that  the hormone production in the ovar is decisive is too far fetched: They have eliminated the entire steroidogenesis in these mice,  therefore the only hormone producing organ of the rescued animals is the transplanted normal ovar. Progestone or other steroid hormones being soluble and acting far away from their place of synthesis could under normal conditions be generated in the adrenal or somewhere else as well. The ovar is by far not the only organ with progesterone synthesis. It will be difficult to answer the question whether the ovar’s progesterone synthesis is required for implantation, since a block in the progesteron synthesis will likely block androgen, estrogen and corticoid synthesis. You would need the 3ß-hydroxysteroid dehydrogenase 1 inactive only in the ovar. And still the animal needs androstendione substitution to allow ongoing testosterone and estrone and thus estradiol synthesis.

Worth to read!