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Photoperiodic Regulation of Type 2 Deiodinase Gene in Djungarian Hamster: Possible Homologies between Avian and Mammalian Photoperiodic Regulation of Reproduction

Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan

Address all correspondence and requests for reprints to: Takashi Yoshimura, Ph.D, Division of Biomodeling, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: takashiy{at}agr.nagoya-u.ac.jp.

Abstract

The molecular mechanisms responsible for seasonal time measurement have yet to be fully described. Recently, we used differential analysis to identify that the type 2 iodothyronine deiodinase (Dio2) gene is responsible for the photoperiodic response of gonads in Japanese quail. It was found that expression of Dio2 in the mediobasal hypothalamus is induced by light and that T₃ content in the mediobasal hypothalamus increased under long day conditions. In addition, we showed that intracerebroventricular infusion of T₃ mimics photoperiodically induced testicular growth. Because it is well known that thyroid hormone is also essential for the maintenance of the seasonal reproductive changes in a number of mammals, we examined expression of Dio2 in Djungarian hamsters and found expression in the ependymal cell layer lining the infralateral walls of the third ventricle and the cell-clear zone overlying the tuberoinfundibular sulcus. Signal intensity was high under long days and weak under short days. Although light pulse did not affect Dio2 expression, melatonin injections decreased Dio2 expression under long days. These results indicate that Dio2 may be involved in the regulation of seasonal reproduction in mammals in the same way as observed in birds.

APPROPRIATE TIMING OF various seasonal processes is crucial to the survival and reproductive success of animals living in temperate regions. Accordingly, seasonal reproduction is conserved among various organisms. Although being the focus of a considerable amount of research, the mechanism of photoperiodism is not well described. Japanese quail are an excellent model for studying photoperiodism because of their rapid and dramatic response to the photoperiod. In birds, the mediobasal hypothalamus (MBH) is considered to be the center for photoperiodic time measurement because: 1) lesion blocks photoperiodic response of gonads even though the GnRH system of the lesioned animal has been left intact (1, 2, 3); 2) electrical stimulation increases LH secretion and induces testicular growth (4); 3) c-Fos is expressed by long day stimulus (5, 6); 4) deep brain photoreceptors are thought to be localized (7); and 5) the circadian clock is localized (8). These observations indicate that all of the essential machinery for photoperiodic time measurement is localized in the MBH. If the center for photoperiodic time measurement is localized in the MBH, then it is expected that some molecular events may occur in the MBH when birds receive long day stimulus. In our recent study on Japanese quail, we used differential subtractive hybridization analysis to identify a gene that is responsible for photoperiodic response of gonads (9). We found that the expression of this gene, type 2 iodothyronine deiodinase (Dio2), is induced by long day stimulus in the MBH. Dio2 is an enzyme which converts prohormone T₄ to bioactive T₃ within a narrow range of concentration (10). T₃ content in the MBH was increased under long days compared with short days, and such differences were not observed in other regions of the brain or in blood. In addition, intracerebroventricular infusion of T₃ mimics photoperiodically induced testicular growth (9). Although thyroid hormones were known to be somehow involved in photoperiodism, our recent study determined both the hormone target site and the molecular events that take place in the brain. Despite the conservation of seasonal reproduction among various species, regulatory mechanism of seasonal reproduction between mammals and birds seems to be quite different. That is, melatonin is critical for mammals, whereas it has no effect in birds (11). Because many studies have indicated that thyroid hormones are also essential for the maintenance of seasonal reproductive changes in a number of mammals (12, 13), we hypothesized that mammals use a similar mechanism for the photoperiodic response of gonads. In this study, we have tested this hypothesis by examining expression of Dio2 in the long day breeder Djungarian hamster.

Materials and Methods

Animals and housing
Djungarian hamsters (Phodopus sungorus) were kept in our colony under 14-h light, 10-h dark conditions. Food and water were provided ad libitum, and sunflower seeds were given once per week. After weaning at 3 wk of age, males were group housed and moved to 8-h light, 16-h dark conditions in light-tight boxes (55 x 210 x 62 cm) to induce testicular regression, according to Milette and Turek (14) with modification. The boxes were placed in a room temperature of 24 ± 1 C. Light was supplied by fluorescent lamps with a light intensity of 200 lux. Short-day animals were kept under short days (8-h light, 16-h dark), and long day animals were transferred to long days (16-h light, 8 h dark) from short days (8-h light, 16-h dark) at 7 wk of age. Brains were collected at 9 wk of age. Animals were treated in accordance with the guidelines of Nagoya University.

Light pulse
Animals were kept under 8-h light, 16-h dark conditions. A single 15-min light pulse was given at zeitgeber time 16, which is within the photoinducible phase. No light was given to control animals. Brains were collected 1 h after the beginning of the light pulse.

Melatonin injection
Eight-week-old hamsters kept under 16-h light, 8-h dark conditions were given daily ip injections of melatonin (Sigma, St. Louis, MO) (10 µg in 0.05 ml 5% ethanol-0.9% NaCl) or vehicle (0.05 ml 5% ethanol-0.9% NaCl) 2 h before lights-out. Injections were given for 8 wk, and animals were killed 8 h after lights-on.

In situ hybridization
In situ hybridization was carried out according to Yoshimura et al. (15). Antisense 45-oligomer oligonucleotide probes of Djungarian hamster Dio2 (5'-tgcttgagtagaatgaccgagtcatagagcgccaggaagaggcag-3') were labeled with [³³P]deoxy-ATP (NEN Life Science Products, Boston, MA) using terminal deoxyribonucleotidyl transferase (Life Technologies, Inc., Frederick, MD). Coronal sections (20 µm thick) were prepared using a Cryostat (Leica CM3050S, Nussloch, Germany). Hybridization was carried out overnight at 42 C. Two high-stringency posthybridization washes were performed at 55 C. The sections were air-dried and apposed to Biomax-MR film (Kodak, Rochester, NY) for 2 wk. ¹⁴C Standards (American Radiolabeled Chemicals, St. Louis, MO) were included in each cassette, and the relative OD was measured using a computed image-analyzing system (MCID, Imaging Research, St. Catherine’s, Ontario, Canada) and converted into the radioactive value (nanocuries) using the ¹⁴C standard measurements. Data were normalized by subtracting the value at the lateral hypothalamic area, which is located in the same section and does not exhibit a hybridization signal. After the exposure to x-ray film, each slide was dipped in type NTB2 autoradiography emulsion (Kodak) and the sections observed with a photomicroscope.

Results

Testicular weight was increased when animals were transferred to long days (Mann-Whitney U test, P < 0.05, n = 3) (Fig. 1). Expression of Dio2 was observed in the ependymal cell layer lining the infralateral walls of the third ventricle and the cell-clear zone overlying the tuberoinfundibular sulcus (Fig. 2A). Signals were also associated with the blood vessels in the arcuate nucleus (ARC). No signal was observed in the sense control (data not shown). Signals were strong under long days and weak under short days in the ependymal cell layer and the cell-clear zone overlying the tuberoinfundibular sulcus (Fig. 2, C–F). A single light pulse at photoinducible phase did not induce Dio2 expression (Mann-Whitney U test, P > 0.05) (see supplemental Fig. 1 published as supplemental data on The Endocrine Society’s Journals Online web site at http://endo.endojournals.org). However, daily melatonin injections significantly reduced the Dio2 expression in the cell-clear zone overlying the tuberoinfundibular sulcus (Mann-Whitney U test, P < 0.05, n = 6) (Fig. 3, A–C). Although similar tendency was observed, no significant difference between melatonin and vehicle injections was observed in the ependymal cell layer (Fig. 3D).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Effect of day length on testicular weight. Mean ± SEM of paired testes weight for 9-wk-old Djungarian hamsters exposed for 2 wk to either 16-h light, 8-h dark conditions [long day (LD)] or 8-h light, 16-h dark conditions [short day (SD)]. Asterisk, P < 0.05 (Mann-Whitney U test, n = 3).

View larger version (91K): [in this window] [in a new window]   FIG. 2. Expression of Dio2 in the hamster hypothalamus. A, Representative dark-field photomicrograph showing the distribution of Dio2 mRNA of long-day animal. Expression of Dio2 was observed in the ependymal cell layer lining the infralateral walls of the third ventricle (arrowhead) and the cell-clear zone overlying the tuberoinfundibular sulcus (bold arrow). Signals were also associated with the blood vessels in the ARC (thin arrow). B, Light-field photomicrograph of serial section stained by Nissl staining. V, Third ventricle. C and D, Representative autoradiograms for Dio2 expression under long days (C) and short days (D). Arrowhead, Ependymal cell layer; arrow, cell-clear zone overlying the tuberoinfundibular sulcus. E and F, Expression of Dio2 is high under long days and low under short days in cell-clear zone overlying the tuberoinfundibular sulcus (E) and the ependymal cell layer (F). Relative OD was measured using computed image-analyzing system and converted into the radioactive value (nanocuries) using the 14C standard measurements. Asterisks, P < 0.05 (Mann-Whitney U test, n = 3).

View larger version (70K): [in this window] [in a new window]   FIG. 3. Effect of melatonin injections on Dio2 expression. Representative autoradiograms from animals given vehicle (A) or melatonin (B) injections under 16-h light, 8-h dark conditions. Vehicle or melatonin injections were given 2 h before lights-out for 8 wk. Arrowhead, Ependymal cell layer; arrow, cell-clear zone overlying the tuberoinfundibular sulcus. Dio2 expression in cell-clear zone overlying the tuberoinfundibular sulcus (C) was decreased in animals that received melatonin injections, whereas no statistical difference was observed in the ependymal cell layer (D). Asterisk, P < 0.05 (Mann-Whitney U test, n = 6).

In the present study, we found expression of Dio2 gene in the ependymal cell layer lining the infralateral walls of the third ventricle, the cell-clear zone overlying the tuberoinfundibular sulcus and surrounding the blood vessels in the ARC. These results were consistent with the previous reports on rat kept under 12-h light, 12-h dark, suggesting the possibility that Dio2 is expressed in the tanycyte in the Djungarian hamster (16). Expression levels were high under long-day conditions and low under short-day conditions. It is noteworthy that in the infundibular nucleus and the median eminence of Japanese quail, Dio2 is strongly expressed under long-day conditions and weakly expressed in short-day conditions (9). These results suggest the possibility that the molecular mechanism for photoperiodic response of gonads may be conserved between Japanese quail and hamsters.

Recently, a number of groups have tried to identify photoperiodically regulated genes in the Djungarian hamster hypothalamus using cDNA microarrays (17, 18). Prendergast et al. (17) found a class of genes encoding T₄-binding proteins (transthyretin, T₄-binding globulin, and albumin) whose expression is associated with reproductive refractoriness to short-day length. In addition, they found reduced hypothalamic T₄ uptake in reproductive refractory animals. It is noteworthy that we found increased T₄ uptake under long photoperiod in Japanese quail (9). In addition, Ross et al. (18) found that genes of the retinoid-signaling pathway, encoding nuclear receptors [retinoid X receptor (RXR)/retinoic acid receptor] and retinoid binding proteins (CRBP1 and CRABP2), are photoperiodically regulated in the hypothalamus and suggested that changes in RXR expression may be associated with seasonal changes in body weight and energy metabolism. RXRs are known to form heterodimers with thyroid hormone receptors (THRs). Distribution of THR () is reported in the hypothalamus of hamster and the sheep (19). Although we did not find photoperiodic regulation of THR and RXR expression, these genes are indeed expressed in the infundibular nucleus and median eminence of Japanese quail (9). It is particularly interesting that results from different species and with different experimental designs all indicate the involvement of thyroid hormone.

It has been suggested that photoperiodic GnRH release could be controlled at the GnRH terminals by glia (6), and thyroid hormones are known to have a critical involvement in the development, plasticity of the central nervous system (10). Recently, we found that GnRH nerve terminals are in close proximity to the basal lamina in birds subjected to long days using immunoelectron microscopy (Yamamura, T., K. Hirunagi, S. Ebihara, and T. Yoshimura, unpublished observations). We also found that the nerve terminal was enclosed by the end feet of glia in short day animals. It is particularly noteworthy that plasticity of GnRH afferents are reported in sheep and hamster, and possible involvement of thyroid hormones are indicated (20).

Although there is little evidence that melatonin controls the reproductive cycles in birds (11), melatonin is a critical factor controlling the photoperiodic response of gonads in mammals (21). Although Dio2 expression was induced by light pulse in the dorsal hypothalamus in the Japanese quail, we found no light induction in the hamster hypothalamus. Therefore, we next examined the effect of melatonin on Dio2 expression. Because chronic melatonin release from beeswax or SILASTIC brand implants (Dow Corning, Midland, MI) can prevent short-day-induced testicular regression (22, 23), we performed daily injection of melatonin according to methods published in previous reports (24, 25). After 8 wk, Dio2 expression in the cell-clear zone overlying the tuberoinfundibular sulcus of melatonin injected animals was decreased compared with expression in the vehicle-injected animals. Although acute effects of melatonin remains to be clarified in future studies, the present study clearly demonstrates that melatonin injections reduce Dio2 expression in the cell-clear zone overlying the tuberoinfundibular sulcus. Recently, it is suggested that different expression profiles of clock genes in the pars tuberalis under different photoperiods decode photoperiodic information (26, 27). Activation of Per genes occur in the early day, whereas activation of Cry genes occur in the early night. This temporal association is conserved even in short and long photoperiods, which result in differences in Per-Cry intervals depending on photoperiod. In mammals, expression of Cry seems to be regulated by melatonin (26), whereas it is driven by light in birds (27). When taken together with the results from the present study, it seems that mammals and birds use similar mechanism for the photoperiodic regulation of reproduction with different mediator (i.e. melatonin and light).

The mechanism that determines long-day breeder or short-day breeder remains unknown. In the short-day breeder ewe, thyroid hormones are required for the seasonal suppression of GnRH and LH secretion, thereby maintaining an annual rhythm in reproductive activity (13). Malpaux et al. (28) have demonstrated that melatonin acts in the premammillary hypothalamic area to control reproduction. Recently, Anderson et al. (29) have demonstrated that chronic T₄ microimplants to premammillary region (including posterior arcuate and ventral premammillary nuclei) in thyroidectomized ewe allow the termination of the breeding season. It seems possible to speculate that expression of Dio2 is photoperiodically regulated around this region in the ewe, and melatonin and T₄ act via Dio2 expressed in this region. This hypothesis remains to be tested in the future study.

Possible homologies between mammalian and avian seasonal reproduction have been discussed for several decades (12, 13). Although many questions remain to be answered, our present study now provides a way in which to analyze homologies between mammalian and avian photoperiodism at the molecular level.

Acknowledgments

We thank Nagoya University Radioisotope Center for use of facilities and Drs. N. Ibuka, K. I. Maeda, and K. Hirunagi for helpful advice.

Footnotes

This work was supported by a supporting grant from the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) (to T.Yo.).

Abbreviations: ARC, Arcuate nucleus; Dio2, 2 iodothyronine deiodinase; MBH, mediobasal hypothalamus; RXR, retinoid X receptor; THR, thyroid hormone receptor.

Received November 24, 2003.

Accepted for publication January 6, 2004.

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