Endocrinology Vol. 148, No. 7 3029-3030
Copyright © 2007 by The Endocrine Society
The Ovary Knows More than You Think! New Views on Clock Genes and the Positive Feedback Control of Luteinizing Hormone
Gregory F. Ball
Department of Psychological and Brain Sciences Johns Hopkins University Baltimore, Maryland 21218
Address all correspondence and requests for reprints to: Gregory F. Ball, Department of Psychological and Brain Sciences, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218. E-mail: gball{at}jhu.edu.
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Introduction
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The molecular revolution in recent decades has transformed many areas of systems physiology. Perhaps in no field has the impact been more significant than in the area of biological clocks. The great success story in this case has been the discovery of clock genes that through a process of coordinated feedback between transcription and translation are able to produce an oscillation that controls many forms of circadian behaviors (1, 2). The paper by Nakao et al. (3) that appears in this issue illustrates clearly how studies based on clock gene expression have the potential to transform our thinking about a classic problem in reproductive neuroendocrinology, in this case the mechanisms controlling the positive feedback of ovarian steroid hormones on LH secretion that results in the LH surge needed for ovulation. To appreciate the significance of this paper, a bit of background on clocks and clock genes should be provided first.
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Clock Genes and the Central vs. Peripheral Control of Physiological Systems
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Clock genes are most often celebrated because of what they tell us about the molecular basis of the clock regulating circadian rhythms. Genes such as per, bmal, and clock have been identified that are expressed in a rhythmic manner in a variety of species including plants as well as invertebrate and vertebrate animal species (1, 2). Based on the identification of these genes and investigations of their interactions, the fundamental clock mechanism can now be discussed with a degree of specificity that one could have only dreamed of as recently as the 1980s. However, there is a second significant implication of the discovery of clock genes that has been particularly important for systems physiology, namely the ability to localize possible sites of clock function anatomically. In the era of research before the discovery of clock genes, there were spirited debates as to how biological rhythms might be controlled by one master clock or by the integration of multiple oscillators (4, 5). In the early 1970s, functional anatomical studies identified the suprachiasmatic nucleus (SCN) as the key site of the "master" circadian clock in mammalian species (6, 7). For a time, the notion reigned supreme that the SCN is the sole or primary site controlling circadian phenomenon either because there is a single clock in the SCN or there are multiple coordinated oscillators within the same brain nucleus. However, there was always some unease about this idea because there were clearly phenomena such as food entrainable rhythms that did not involve the SCN (8). With the discovery of clock genes, it became clear that there are indeed multiple oscillators throughout the body that can possibly control vertebrate circadian rhythms independently of the SCN. For example, studies using a PERIOD2::LUCIFERASE fusion protein as a real-time reporter of circadian dynamics in mice have found that peripheral tissues such as the kidney and lung can produce self-sustained circadian oscillations for up to 20 d. Also, lesions to the SCN did not abolish rhythmic clock gene expression in any peripheral tissue, although such lesions did result in a desynchronization of peripheral oscillators (9).
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Circadian Rhythms and Ovulation
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What does the establishment of multiple oscillators in the brain and periphery have to do with positive steroid feedback and the control of ovulation? The switch from negative to positive feedback that ovarian steroids exert on LH release is one of the most complex and challenging aspects of the neuroendocrine control of reproduction. This switch to positive feedback is essential for triggering the LH surge that in turn stimulates ovulation. In mammals, positive feedback is implemented by estradiol, whereas in birds ovarian progesterone is the key hormone. It has been clear for many years based on studies in birds and mammals that the regulation of positive feedback has a circadian component. For example, classic studies by Everett and Sawyer (10) in rats demonstrated that there is only a limited window in the circadian cycle during which the LH surge can be initiated. This periodicity in the LH release mechanism constitutes a "true" circadian rhythm, and there is evidence that the SCN has to be intake for it to be maintained (11) and that clock gene genes must be functioning normally (12).
The study of ovulation in domestic fowl and other gallinaceous birds has been a topic of intense study because of its obvious practical and commercial interest (13). Chickens lay eggs on a 24- to 27-h cycle so that on each day, egg laying occurs later in the day until a "rest" day occurs after which ovulation is initiated again (13). The daily oviposition cycle is entrained by light, and similar to what was observed in mammals, a 6- to 10-h daily period has been identified when progesterone positive feedback is effective in stimulating the LH surge and initiating ovulation followed by oviposition (14, 15). The prevailing view has been that this circadian process was controlled by central oscillators such as those in the SCN. The study by Nakao et al. (3) published in this issue of Endocrinology challenges this view. They report that clock genes per 2 and 3 as well as clock and baml1 are expressed in preovulatory follicles. Diurnal changes in per 2 and 3 expression occur in the largest follicle that is first in line to ovulate but not in smaller follicles in line behind it. Do these changes in clock gene expression mean anything for the control of ovulation? A gene related to increased synthesis of progesterone, steroidogenic acute regulatory protein (StAR), was found to exhibit a 24-h cycle in the largest follicle coincident with the expression of per 2. The exciting implication of this work is that LH induction of progesterone synthesis is gated by a circadian rhythm in clock gene expression in the largest follicle next in line to ovulate. Evidence supporting this notion is also provided in the Nakao et al. (3) study in that they show that the 5' flanking region of the StAR gene contains E-box enhancers, which can bind to CLOCK/BMAL1 heterodimers to activate gene transcription. Thus, a plausible mechanism exists by which clock gene expression in ovarian follicles could initiate the synthesis of progesterone needed for positive feedback effects on LH.
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General Implications of the Work
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This study by Nakao et al. (3) provides a new scenario for the circadian control of ovulation. Instead of the brain alone being the site of information integration relevant to ovulation as well as the source of the circadian clock gating the timing of ovulation, the circadian gate on the timing of the LH surge would reside in the ovary itself, perhaps in the largest follicle next in line to ovulate. This would change our view of the relationship between the ovary and the brain; they could be viewed as more balanced partners in regulating the LH surge and ovulation rather than the gonad being a somewhat passive recipient of timed instructions from the brain. Such a change in view is not merely semantic but can change our view about where and how to investigate the regulatory processes that control the LH surge, ovulation, and oviposition. However, it is important to note that these studies reported by Nakao et al. (3) are only a first step. More studies are needed to confirm the validity of this scenario and nail down causal connections between events that are at present only established as correlations. For example, a more thorough analysis of the clock gene expression in the follicles is needed to show that it is truly circadian. Also causal links need to be established between StAR expression and ovulation. These are challenges for the future but Nakao et al. (3) have taken a significant step in reorienting our thinking.
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Footnotes
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Disclosure Statement: The author has nothing to disclose.
Abbreviations: SCN, Suprachiasmatic nucleus; StAR, steroidogenic acute regulatory protein.
Received April 30, 2007.
Accepted for publication May 1, 2007.
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References
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Introduction
Clock Genes and the...
