Abstract
Many animals that breed seasonally measure the day length (photoperiod) and use these measurements as predictive information to prepare themselves for annual breeding. For several decades, thyroid hormones have been known to be involved in this biological process; however, their precise roles remain unknown. Recent molecular analyses have revealed that local thyroid hormone activation in the hypothalamus plays a critical role in the regulation of the neuroendocrine axis involved in seasonal reproduction in both birds and mammals. Furthermore, functional genomics analyses have revealed a novel function of the hormone thyrotropin. This hormone plays a key role in signaling day-length changes to the brain and thus triggers seasonal breeding. This review aims to summarize the currently available knowledge on the interactions between elements of the thyroid hormone axis and the neuroendocrine system involved in seasonal reproduction.
Photoperiodism
Many animals inhabiting regions in the temperature zone limit their reproductive activity to specific seasons in order to maximize the survival of their offsprings. Species that have a short incubation or gestation period, such as birds and small mammals, produce young during spring and summer; therefore, they are known as long-day breeders. By contrast, species that have a gestation period of about 5 or 6 months, such as sheep, goats, and deer, enter breeding in the autumn; therefore, they are known as short-day breeders. These seasonal breeding animals use the changes occurring in the day length (photoperiod) as a calendar and accordingly regulate many of their physiological and behavioral processes, including reproduction, migration, molting, hibernation, and body weight alterations. In long-day breeders, the increase in the photoperiod during spring stimulates the secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus and the subsequent release of gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) from the pituitary gland. By contrast, the decrease in the photoperiod during autumn stimulates the secretion of these hormones in short-day breeders. This phenomenon is termed as ‘photoperiodism’. Prolactin secretion is also known to be photoperiodically regulated (reviewed by Morgan & Williams 1996). However, its release is not driven by thyroid hormones (Dahl et al. 1994). Furthermore, previous studies have revealed that the blockade of seasonal reproductive functions due to lesions or hypothalamo-pituitary disconnection does not affect the seasonal secretion of prolactin (Juss 1993, Lincoln 2002). Therefore, we do not focus on prolactin in the present review.
Melatonin and seasonality
In all vertebrates, melatonin is secreted on a daily basis by the pineal gland under the control of the circadian system; its secretion peaks during the subjective night and ceases during the day. The duration of melatonin secretion tracks night length and in mammal this humoral signal is considered a crucial component of the mechanism governing mammalian photoperiodism (Reiter 1993, Goldman 2001). In mammals, light signals are received by the eye and are then transmitted to the circadian pacemaker in the hypothalamus, i.e., the suprachiasmatic nucleus (SCN). The SCN drives the nocturnal rhythm of melatonin secretion by the pineal gland, and a lesion in the SCN abolishes the circadian rhythms that govern the production and secretion of this hormone (Scott et al. 1995, Tessonneaud et al. 1995). Hamsters and sheep have been shown to develop photoperiodic blindness following pinealectomy (Hoffman & Reiter 1965, Bittman et al. 1983). In addition, melatonin secretion for a long duration (i.e., short-day pattern) suppresses gonadotropin secretion in hamsters (Bartness et al. 1993) but stimulates it in sheep (Bittman & Karsch 1984). Melatonin is considered to act on its membrane-bound receptors that are involved in the regulation of a various seasonal responses. Specific melatonin-binding sites have been identified by using 125I-labeled melatonin, and a study wherein lesions were created in melatonin-binding sites revealed that the mediobasal hypothalamus (MBH) is essential for the melatonin-mediated photoperiodic control of reproduction in hamsters (Maywood et al. 1996). It has also been reported that microimplants of melatonin introduced into the MBH of sheep regulate seasonal reproduction; this suggests that the MBH plays an important role in the photoperiodic mechanisms that operate in mammals (Lincoln 1992, Lincoln & Maeda 1992, Malpaux et al. 1993). Although melatonin plays a critical role in the photoperiodic mechanisms as mentioned above, the downstream pathway involved in its functioning remains unknown.
Birds, just like mammals, secrete a daily rhythm of melatonin that tracks night length but, surprisingly, melatonin is not involved in the photoneuroendocrine axis regulating gonadotropin secretion and seasonal breeding (Kumar et al. 1993). Light is detected directly within the brain of birds via deep brain photoreceptors, and eyes are not required for this process. Despite the marked differences that exist between the mammalian and avian light input pathways for the regulation of photoperiodism, the MBH is considered the center for photoperiodic time measurement in both mammals and birds. This is because lesions in the MBH block photoinduced LH release (Sharp & Follett 1969, Davies & Follett 1975) even though the GnRH neurons are left intact (Juss 1993) and deep brain photoreceptors are thought to be localized in this region (Silver et al. 1988, Saldanha et al. 1994). In addition, circadian clock genes are expressed in the MBH, and the circadian clock they regulate appears to be the long-sought biological clock responsible for photoperiodic time measurement (Ball & Balthazart 2003, Yasuo et al. 2003).
Thyroid hormones and seasonality
For many decades, it has been known that interference with the thyroid glands (or exogenous treatment with thyroid hormones) has a wide range of effects upon seasonal reproduction in birds (recently summarized by Dawson & Thapliyal 2001). Two major sets of effects have been described. First, exogenous treatment with thyroid hormones has been shown to mimic the effects of long-day conditions. Additionally, thyroid gland removal stops the development of photorefractoriness (i.e., insensitivity to previous stimulatory day-length) in birds and if carried out during the refractory period leads to its spontaneous dissipation (Follett & Nicholls 1988, Goldsmith & Nicholls 1992, Wilson & Reinert 1995, Bentley et al. 1997). Most of the molecular analyses described below have focused upon the involvement of thyroid hormones in long-day induced gonadotropin secretion and it is still unclear exactly how the thyroid is involved in refractoriness (refer to Dawson 1993, Dawson et al. 2001).
Fascinatingly, studies have shown that the thyroids are also involved in mammalian seasonal responses. In sheep, thyroidectomy stops the development of refractoriness in ewes (Nicholls et al. 1988) and rams (Parkinson & Follett 1994, 1995). Work from Michigan and New Zealand groups suggests that then thyroid hormones are probably involved in the alterations in the responsiveness of the GnRH axis to the negative feedback effects of estrogen during the transition to anestrus (Moenter et al. 1991, Anderson et al. 2002). Although possible homologies between the avian and mammalian photoperiodic systems have been discussed, the precise role played by thyroid hormones in the regulation of seasonal reproduction has remained unclear for many decades.
The Japanese quail – an excellent model for studying photoperiodism
Although the mouse is a superb vertebrate model for many physiological processes, this is not true for seasonality and so work has focused upon species showing far stronger photoperiodic responses (quail, starlings, and white-crowned sparrows; sheep and hamsters). The Japanese quail (Coturnix japonica) offers some advantages when studying real-time photoperiodic changes. Quail respond to a single long day. Put briefly, photoperiodic induction occurs when light coincides with one particular phase of a circadian based rhythm of photoinducibility (Follett & Sharp 1969). In quail, the most sensitive phase of this rhythm begins about 11 h after dawn and runs until about 1600 h. If light occurs during this period (as in a long day) then a wave of gonadotropin secretion is triggered. The first detectable changes in LH, FSH, and GnRH secretion begin at about 2200 h of the first long day and a wave of secretion builds up over the next few days (Follett et al. 1977, Nicholls et al. 1983).
Molecular analysis of photoperiodic time measurement
We offered the hypothesis that in quail given light pulses during the photoinducible phase there would be molecular events induced within the MBH where the center for photoperiodic time measurement is localized. Based on this assumption, a differential subtractive hybridization analysis was performed by using the MBH of a quail that received light pulse and no light pulse at the photoinducible phase. From the analysis emerged one key gene encoding type 2 iodothyronine deiodinase (DIO2; D2) (Yoshimura et al. 2003). Acute induction of DIO2 expression by light was observed in the dorsal MBH, around the paraventricular organ. Furthermore, upregulation of DIO2 was observed in the ependymal cells lining the ventrolateral walls of the third ventricle and the infundibular nucleus (which is anatomically homologous to the mammalian arcuate nucleus) by the continuous long-day stimulus (Fig. 1). These observed photoinduced expression sites of DIO2 were in agreement with the results of lesion studies performed by Sharp & Follett (1969). This suggests that DIO2 expression in both regions is potentially important for the induction of photoperiodic responses in the gonads (Yoshimura et al. 2003).
Expression of DIO2 and DIO3 in the MBH. Dark-field photomicrographs of the DIO2 and DIO3 expressions and a light-field photomicrograph of the Nissl-stained sections are shown. The images of DIO2 and DIO3 expressions were obtained from continuous long- and short-day stimulated birds respectively. EC, ependymal cell layer lining the ventrolateral walls of the third ventricle; ME, median eminence; and IIIV, third ventricle.
Citation: REPRODUCTION 136, 1; 10.1530/REP-08-0041
Local activation of thyroid hormone is the key for the photoperiodic response
A further discovery was that the expression of type 3 iodothyronine deiodinase (DIO3) was downregulated under long-day conditions at the same time as DIO2 was upregulated (Yasuo et al. 2005). The timing of the inverse changes was precise and began at about 16–18 h on the first long day to which the quail were exposed. This was some 4 h prior to first detectable rise in LH secretion. A strong argument that the DIO2/DIO3 changes were related to photoinduction came from finding that the gene changes lasted for a number of days after quail had been exposed to just one long photoperiod, just as occurred in the case of LH secretion. The enzyme DIO2 (D2) catalyzes the removal of an outer ring iodine from the prohormone thyroxine (T4) and thus converts it into the bioactive form, i.e., 3,3′,5-tri-iodothyronine (T3). By contrast, the enzyme DIO3 (D3) catalyzes the removal of an inner ring iodine from T4 and T3 and thus converts them into reverse T3 (rT3) and T2 respectively (Fig. 2; Leonard & Visser 1986). Thus, both these enzymes play essential roles in the local control of the T3 levels via mechanisms that operate under a various conditions to maintain the T3 concentrations within a narrow range (Bernal 2002). Overall, it appeared as if the DIO2/DIO3 changes had the capacity to produce locally high concentrations of the T3, the active thyroid hormone. Support for this idea came from finding that the T3 concentrations in the MBH of the quail were found to be approximately ten times higher under long- than short-day conditions, while these concentrations in the plasma and other parts of the brain, such as the optic tectum and cerebellum, did not differ with the exposure conditions (Yoshimura et al. 2003).
Structures and interrelationships between the principal iodothyronines in activated or inactivated form. Type 2 deiodinase (DIO2) generates active T3 from T4 by outer ring deiodination, whereas type 3 deiodinase (DIO3) catalyzes the conversion of both T3 and T4 to inactive form by inner ring deiodination.
Citation: REPRODUCTION 136, 1; 10.1530/REP-08-0041
Next, to validate the physiological significance of this local activation of the thyroid hormone, the effects of i.c.v. infusion of T3, T4, and a DIO2 inhibitor were investigated. Although the effects of T4 infusion on testicular growth were minimal, T3 administration under short-day conditions mimicked the effects of long-day conditions on testicular growth. In addition, i.c.v. infusion of a DIO2 inhibitor, namely iopanoic acid, impaired testicular growth under long-day conditions (Yoshimura et al. 2003). These results clearly indicated that the local activation of the thyroid hormone within the MBH, induced by long-day conditions, plays a key role in the regulation of seasonal reproduction.
Extension of findings to photoperiodic mammals
At this point, a number of studies were undertaken by both ourselves and others that indicated that the DIO2/DIO3 discoveries may also apply in a number of photoperiodic mammals. Although some interspecies differences exist with regard to the relative importance of DIO2 and DIO3 in photoperiodism, the photoperiodic regulation of DIO2 and/or DIO3 expression has been confirmed in various mammalian species, including the Djungarian (Siberian) hamster (Watanabe et al. 2004, 2007, Barrett et al. 2007, Freeman et al. 2007), Syrian hamster (Revel et al. 2006, Yasuo et al. 2007a), rat (Yasuo et al. 2007b), and goat (Yasuo et al. 2006). Further, T3 administered exogenously under short-day conditions was observed to mimic the effects of long-day conditions on gonadal growth in hamsters (Barrett et al. 2007, Freeman et al. 2007). In addition, it has been reported that the expressions of DIO2 and DIO3 are regulated by melatonin in mammals (Watanabe et al. 2004, Revel et al. 2006, Barrett et al. 2007, Yasuo et al. 2007a). It is also noteworthy that in goats, which breed under short-day conditions, a long-day stimulus suppressed the expression of DIO2; this effect was contrary to that observed in species that breed under long-day conditions (Yasuo et al. 2006). In the ewe, the function of the thyroid hormone in suppressing seasonal activity is known to be limited to a specific seasonal window (Thrun et al. 1997, Billings et al. 2002), and the long-day suppression of DIO2 expression may provide a mechanism that accounts for the lack of responsiveness to T4 during the mid to late anestrus (Yasuo et al. 2006).
Thyroid hormone uptake in the MBH
For a long time, it was believed that the thyroid hormone traverses the plasma membrane via passive diffusion due to its lipophilic nature. However, recent studies have revealed the existence of thyroid hormone transporters. Prendergast et al. (2002) reported that the expression patterns of thyroid hormone transporters such as transthyretin, T4-binding globulin, and albumin in Siberian hamsters differ following exposure to short- and long-day conditions. These transporters may be involved in the regulation of seasonal breeding in mammalian species. However, genes encoding these transporters were not observed to be expressed in the MBH of quail. On the contrary, in quail, organic anion transporting polypeptide 1c1 (OATP1C1) has been demonstrated to transport T4 from the cerebrospinal fluid (CSF) in the third ventricle to the ependymal cells lining the ventrolateral walls of the third ventricle, where DIO2 and DIO3 are expressed (Nakao et al. 2006). This indicates that OATP1C1 may play a role in the cellular uptake of T4 from the CSF to ependymal cells. Following this uptake, T4 is intracellularly converted either into active T3 due to the high DIO2 expression induced by long-day conditions or into inactive rT3 due to the high DIO3 expression induced by short-day conditions.
Downstream events of thyroid hormone action
Thyroid hormone exerts its effects via its nuclear receptors. In quail, weak mRNA expression of the thyroid hormone receptors α (THRA) and β (THRB) and strong mRNA expression of the retinoid X receptor α (RXRA) have been observed in the basal tuberal hypothalamus (BTH), which includes the median eminence and infundibular nucleus (Yoshimura et al. 2003); this indicates that the BTH is the target site for T3 action. Thyroid hormones are known to be critically involved in the development, plasticity, and functioning of the central nervous system (CNS; Bernal 2002). Therefore, immunoelectron microscopy of the median eminence was performed for quail under both short- and long-day conditions. The nerve terminals of the GnRH neurons were observed to be in close proximity to the basal lamina under long-day conditions, while they were encased by the endfeet of the glial processes under short-day conditions (Yamamura et al. 2004). The administration of T3 into the brain brought about similar morphological changes and induced testicular growth under short-day conditions (Yamamura et al. 2006). In the glial cells of the median eminence, Fos-like immunoreactivity is induced by long-day stimulus, and this suggested that GnRH release may be controlled by the glial cells at the level of the nerve terminal (Meddle & Follett 1997). Thus, morphological changes in the GnRH neurons and glial processes may regulate the seasonal secretion of GnRH.
A functional genomics analysis of photoperiodic induction in quail
The chicken genomic sequence data, which have recently been made available, have permitted the expansion of studies on avian species from single-gene to genome-wide transcriptional analyses. To analyze the system dynamics and network structure in the MBH involved in regulating the photoperiodic activation of the thyroid hormone in the quail, which is a galliform bird closely related to the chicken, functional genomics analysis was performed using a chicken high-density oligonucleotide microarray (Affymetrix Chicken Genome Array) during the photoinduction process in quail exposed to an abrupt shift from short to long days (Nakao et al. 2008). The analysis (Fig. 3) identified two waves of gene expression. As found previously, there was upregulation of DIO2 and downregulation of DIO3, which began at about 1800–1900 h. This wave of gene change was accompanied by alterations in another nine genes including ICER, NR4A3, and CEBPB. Of particular interest, however, was a wave of gene expression that began a few hours earlier at about 1400 h of the first long day. In particular two genes, thyroid-stimulating hormone β (TSHB) and eyes absent 3 (EYA3), rose rapidly (Fig. 3) on the first long day and showed another wave of induction on day 2. The timing of these two first wave genes is fascinating since it coincides with the phase of photoinducibility (Nicholls et al. 1983, Follett et al. 1998) while earlier experiments had indicated that by 1400 h a quail understands that it has been exposed to a long day even if LH secretion has not yet begun (Follett et al. 1977). A spatio-temporal expression analysis of the genes that produced the first and second expression waves revealed that these genes are localized in the pars tuberalis of the pituitary gland and in the ependymal cells lining the ventrolateral walls of the third ventricle in the MBH respectively. The pars tuberalis is a part of the adenohypophysis and is a highly vascularized multicellular tube of cells that surrounds the hypophyseal stalk (Stoeckel & Porte 1984). Although EYA3 encodes a transcriptional coactivator, it seems unlikely that it regulates the expression of the second wave genes because its localization in the pars tuberalis is distinct from those of the second wave genes in the ependymal cells. On the other hand, TSHB encodes the β-subunit of TSH. Functional TSH requires two noncovalently linked subunits, a common pituitary glycoprotein α-subunit (CGA) and TSHβ. In addition to TSHB expression, CGA expression was observed in the pars tuberalis, and the photoinduction of TSHβ-like immunoreactivity was confirmed in the pars tuberalis. The expression of TSH receptor (TSHR) was observed in the ependymal cells lining the ventrolateral walls of the third ventricle, where the second wave genes are expressed, and the binding of 125I-labeled TSH was confirmed in this region. Since the median eminence is located outside the blood–brain barrier, it can be hypothesized based on our results that TSH induced in the pars tuberalis by long-day conditions acts on the TSHR localized on the ependymal cells in the MBH, where the second wave genes are expressed.
Identification of waves of gene expression during the photoinduction process. Induction of the first wave genes comprising the TSHB and EYA3 genes was followed by induction of the second wave genes, which included the DIO2 and DIO3 genes. Data were normalized such that the median signal strength for each gene over all time points was 1.0. The average signal strength at each point was then displayed as a ratio relative to the median signal strength of that gene. Expression of the first wave genes was observed in the pars tuberalis (PT), whereas that of the second wave genes was observed in the ependymal cell (EC) and the infundibular nucleus (IN). The time of 0 h corresponds to the dawn of the first long day.
Citation: REPRODUCTION 136, 1; 10.1530/REP-08-0041
Pars tuberalis TSH triggers DIO2 expression
The hypothesis that TSH triggers the expression of second wave genes was tested by i.c.v. injection of TSH and an anti-TSHβ antibody. TSH administration induced the expression of the second wave genes, including DIO2, in a dose-dependent manner, whereas the immunoneutralization of TSH by the administration of anti-TSHβ IgG impaired their expression that had been induced by long-day conditions. These results clearly indicated that TSH released in the pars tuberalis induces the expression of second wave genes. TSH is known to function via the TSHR-Gsα-cAMP signaling pathway. When the promoter sequences of the second wave genes, including DIO2, ICER, NR4A3, and CEBPB, were determined in the quail and chicken, cAMP responsive elements were found to be highly conserved among these genes in both species. In addition, promoter analysis performed using the luciferase reporter revealed that TSH released in the pars tuberalis triggers the second wave gene expression via the TSHR-cAMP signaling pathway.
By subsequent microarray analysis, 183 genes were identified, whose expression patterns in the MBH differed between short- and long-day conditions. Among these genes, TSHB and CGA were observed to be markedly upregulated under long-day conditions. Therefore, the effects of chronic TSH administration on testicular growth were investigated. As expected, this TSH administration induced DIO2 expression and testicular growth. These results suggest that TSH released in the pars tuberalis under long-day conditions is important not only for the process of photoinduction but also for the maintenance of reproductive functions.
Conclusion
Although the involvement of the thyroid hormone in the regulation of seasonal reproduction has long been recognized, its localization and the manner in which it exerts its function in this regard have remained unclear. Recent molecular analyses have revealed that local activation of the thyroid hormone by DIO2 and DIO3 in the MBH plays a critical role in the regulation of seasonal reproduction in both birds and mammals.
It has been reported that the expression of CGA and TSHβ in the mammalian pars tuberalis are photoperiodically regulated (Wittkowski et al. 1988, Bockmann et al. 1996, 1997). Furthermore, the expression of TSH has been detected in the CSF and CNS (Schaub et al. 1977, Hojvat et al. 1982) of mammals. In addition, TSHR has been reported to be expressed in the mammalian brain. The localization of melatonin receptors on the pars tuberalis suggests a photoperiodic function of the pars tuberalis in mammals (Morgan & Williams 1996). However, the functional significance of TSH induction in the pars tuberalis with regard to the control of photoperiodic responses has remained unclear for many decades. Recent functional genomics analyses have demonstrated that TSH expression induced in the pars tuberalis by light stimuli triggers DIO2 expression in the MBH in birds (Fig. 4). These findings shed light on an entirely novel function of the pituitary hormone TSH and provide deeper insights into the functional significance of the pars tuberalis in birds. Future studies should aim to confirm whether TSH released in the pars tuberalis mediates the melatonin signal to DIO2/DIO3 expression in mammals. Further, the primary objective of immediate future research should be to identity the photoperiodic signaling pathway that activates the TSH in the avian pars tuberalis.
A model depicting a possible mechanism whereby thyroid hormones can regulate the photoperiodic response in birds. Light information received by the deep brain photoreceptors induces the expression of TSHB in the pars tuberalis (PT) of the pituitary gland. The light input pathway to the PT remains unknown. Long-day-induced TSHβ and cycling CGA (common pituitary glycoprotein α-subunit) form TSH in the PT and act on the TSH receptor (TSHR) localized in EC. Expression of the second wave genes that include DIO2 is induced by TSH through the TSHR-cAMP signaling pathway.
Citation: REPRODUCTION 136, 1; 10.1530/REP-08-0041
Acknowledgements
This work was supported in part by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN), Grant-in-Aid for Scientific Research (B), and Grant-in-Aid for Young Scientists (S) from the JSPS to T Y. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
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