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Keywords:

  • deiodinase;
  • hypothalamus;
  • pars tuberalis;
  • tanycytes;
  • thyroid hormone

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

Abstract:  Seasonal mammals typically of temperate or boreal habitats use the predictable annual cycle of daylength to initiate a suite of physiological and behavioural changes in anticipation of adverse environmental winter conditions, unfavourable for survival and reproduction. Daylength is encoded as the duration of production of the pineal hormone melatonin, but how the melatonin signal is decoded has been elusive. From the studies carried out in birds and mammals together with the advent of technologies such as microarray analysis of gene expression, progress has been achieved to demystify how seasonal physiology is regulated in response to the duration of melatonin signalling. The critical tissue for the action of melatonin is the pars tuberalis (PT) where melatonin receptors are located. At the molecular level, regulation of cyclic adenosine monophosphate (cAMP) signalling in this tissue is likely to be a key event for melatonin action, either an acute inhibitory action or sensitization of this pathway by prolonged stimulation of melatonin receptors reflecting durational melatonin presence. Melatonin action at the PT has been shown to have both positive and negative effects on gene transcription, incorporating components of the circadian clock as part of the mechanism of decoding the melatonin signal and regulating thyrotrophin-stimulating hormone (TSH) expression, a key output hormone of the PT. Microarray analysis of gene expression of PT tissue exposed to long and short photoperiods has identified important new genes that may be regulated by melatonin and contributing to the seasonal regulation of TSH production by this tissue. In the brain, tanycytes lining the third ventricle of the hypothalamus and regulation of thyroid hormone synthesis by PT-derived TSH in these cells are now established as an important component of the pathway leading to seasonal changes in physiology. Beyond the tanycyte, identified changes in gene expression for neuropeptides, receptors and other signalling molecules pinpoint some of the areas of the brain, the hypothalamus in particular, that are likely to be involved in the regulation of seasonal physiology.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

The annual cycle in daylength is accompanied by an annual fluctuation of environmental temperature and food availability. Mammals have evolved different strategies to overcome the challenges of low temperatures and reduced food supply and include some remarkable adaptations in physiology. These adaptations include timing of reproductive activity to produce offspring at an optimal time of year when food supply should be plentiful. Other aspects of physiology which may be adapted for survival through the winter included most typically the enhancement of adipose energy stores during summer and a seasonal moult to provide an appropriate pelage to maintain body temperature and pelage colour for camouflage.

Mammals have evolved a mechanism to translate the predictable annual cycle of daylength to anticipate the onset of adverse conditions in winter or favourable conditions in summer to adapt physiology and behaviour appropriate for the approaching season.

At the heart of this mechanism is the nocturnal pineal hormone melatonin. Melatonin was discovered more than 50 yr ago [1], and a relatively short time later was shown to be the principal hormone involved in changing reproductive physiology in seasonally breeding mammals. The breakthrough emerged when it was demonstrated that pinealectomized male hamsters held in short photoperiod lost the ability for gonadal regression [2]. Later, it was demonstrated that an intact pineal gland was also required for seasonal involution of the reproductive system in hamsters kept under natural photoperiod [3]. Whilst it was suspected that melatonin may be the active agent in mediating gonadal involution in the seasonally breeding hamster, the definitive evidence for melatonin’s involvement came from experiments demonstrating infusion of melatonin into Siberian hamsters causes gonadal regression [4]. The regulation of melatonin synthesis by the pineal gland was established to be under the control of light perception by the eye and then subsequently transmitted via a neuronal pathway (retinohypothalamic tract) to the suprachiasmatic nucleus (SCN), the master biological clock [5]. The SCN controls melatonin secretion by the pineal gland through a polysynaptic pathway transmitted via the superior cervical ganglion to restrict melatonin synthesis and secretion to the night. Therefore, when the night length is long, the duration of melatonin secretion is long (winter) and when the night length is short, the duration of melatonin secretion is short (summer). Thus, melatonin is the endocrine representation of the period of darkness, inversely reflecting photoperiod length. With respect to implementing physiological adaptations, the key element of the melatonin signal is duration rather than the amplitude of the melatonin signal [4], but how the changing duration of melatonin is decoded to produce a seasonal change in physiology remains a great challenge.

The evidence accumulated to date related to the molecular processes by which the pineal gland and melatonin-mediate seasonal reproduction events has provided a somewhat unexpected relationship between the action of melatonin and translation to seasonal physiological and behavioural responses. Whilst it was widely anticipated melatonin would act in the brain to implement changes in reproductive physiology or energy balance mechanisms, what transpires from the best evidence to date is a relationship between the pars tuberalis (PT) of the pituitary stalk, the tanycytes lining the third ventricle and hypothalamic neurons regulating seasonal physiology.

The pars tuberalis

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

In vitro autoradiography and in situ hybridization studies have identified areas of the brain that express melatonin receptors and could potentially transduce seasonal variations in daily nocturnal melatonin profiles [6]. However, among seasonal mammals, there is no common region of the brain where melatonin receptors are expressed that may account for melatonin’s action to coordinate seasonal responses. Nevertheless, one common site emerges from these studies as a site for the action of melatonin among seasonal species, and surprisingly this is not located in the brain but in the PT, a circular sheath of pituitary tissue on the base of the brain, which for decades was considered to be physiologically insignificant. However, in the seasonally breeding ferret, this is the only site where melatonin receptors are found [7].

Melatonin receptors are abundantly expressed in the PT and tissue availability from sheep afforded a model tissue for studying the mode of action of melatonin [8, 9]. Studies on PT cells established the melatonin receptor as G-protein-coupled receptor primarily linked to the acute inhibition of cyclic adenosine monophosphate (cAMP) synthesis [8]. Intriguingly, chronic melatonin treatment of PT cells sensitizes adenylate cyclase enzymes such that upon removal of melatonin, basal levels of cAMP can rise without further stimulation and can be greatly enhanced by activators of adenylate cyclase [10–12]. The role of sensitization as a component of the molecular mechanism of melatonin’s action is not entirely clear. It would be natural to assume that sensitization of PT cells would be more important as a relay signal in short days (SD), but this does not necessarily follow. Firstly, melatonin causes sensitization of adenylate cyclase to forskolin stimulation in PT cells within 8 hr of chronic melatonin exposure [13], with a similar response observed in CHO cells transfected with the melatonin receptor [14]. Secondly, rises in PT basal levels of cAMP observed with a chronic treatment of melatonin in vitro may be insufficient to initiate an action in vivo or could be suppressed by another receptor coupled to inhibition of cAMP. Thirdly, it may require the coincidence of activation of a receptor coupled to cAMP stimulation to implement the advantage of the sensitized state, and this may apply either in LD melatonin- or SD melatonin-exposed cells. It is interesting to note that sensitization of the cAMP signal transduction pathway is greatly enhanced by the tyrosine kinase inhibitor, herbimycin [10–12], possibly reflecting a balance between a tyrosine kinase and phosphatase activity which may be important to the mechanism of sensitization. It is noteworthy, therefore, that when sheep are transferred from SD to LD, among the first genes in PT cells to be induced is Eya3 [15–17], a protein that has a dual function as a transcriptional activator and a protein tyrosine phosphatase [18].

Adenosine and PACAP have been identified as hormonal ligands which can induce cAMP in explants or cultures of sensitized PT cells [11, 19]. However, if there is a role for PACAP in vivo, such a role will be an indirect one as in situ hybridization studies in sheep revealed PACAP receptors to be present on cells located in the median eminence adjacent to the PT and not in PT cells [11, 12].

Recent studies related to a functional role of the thyroid hormone system have identified regulated thyroid-stimulating hormone (TSH) synthesis in the PT as well as TSH receptors (TSH-R) in ovine PT cells. TSH can activate cAMP synthesis via TSH-R, a Gs-coupled G protein-coupled receptor [20]. Furthermore, TSH, [a heterodimeric complex of a common alpha-glycoprotein subunit [α-GSU] and specific TSHβ subunit], is upregulated with LD exposure. Consequently, this could provide a positive feedback loop to increase cAMP and where sensitization by melatonin may amplify the input signal to activate downstream pathways including gene transcription (Fig. 1).

image

Figure 1.  A model for interactions between adenylate cyclase (cAMP) generation, transcription factors and the production and secretion of TSH in a melatonin responsive cell of the pars tuberalis (PT). In long days/short nights, cAMP may be elevated to a concentration to elicit expression of transcription factors leading to increased expression of TSH – a dimer of a specific TSHβ subunit and alpha-subunit (αGSU) common to glycoprotein hormones. Increased expression and secretion of TSH passes through to tanycytes of the third ventricle to regulate thyroid hormone availability in the hypothalamus. TSH, acting as a paracrine factor, has the potential to increase cAMP-mediated transcription on the PT through a mechanism that may involve sensitization of the adenylate cyclase enzyme by a melatonin receptor-mediated event. During longdays/short nights, Cry1 induction by the evening rise in melatonin is sufficiently temporally separated from Per1 induction, which follows shortly after the night time decline in melatonin production, to prevent sufficient amounts of a Per1/Cry1 inhibitory transcriptional complex. In short days/long nights, induction of Cry1 by melatonin is temporally closer to Per1 induction allowing Per1/Cry1 inhibitory complexes to become more prevalent. The complexes may then inhibit Clock/Bmal1 transcriptionally regulated events. This together with a reduced drive from cAMP-mediated transcriptional activity may decrease TSH production with a reduction in the TSH drive on tanycytes.

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Although melatonin would be expected to have a negative impact on gene transcription via an acute inhibition of the cAMP signal transduction pathway, chronic melatonin action resulting in sensitization provides a possible stimulatory mechanism by which melatonin could influence the PT transcriptome for effecting seasonal physiology. Recently, it was shown that melatonin has an acute stimulatory action on gene transcription, promoting transcription of the TSH-R and notably the clock gene Cry1 [21, 22]. The signal transduction pathway leading to the induction of the TSH-R and Cry1 is unknown, but the potential of the melatonin receptor to couple parallel signal transduction pathways offers one avenue for exploration [23, 24].

The induction of Cry1 by melatonin is likely to be an important interface between melatonin and decoding the signal of melatonin duration. The identification of components of the molecular clockwork and the self-sustaining feedback loops that drive the master circadian pacemaker of the SCN has provided the basis for the lines of investigation underpinning molecular mechanisms for decoding of the melatonin signal.

The molecular basis of the circadian clock centres around a positive transcriptional arm composed of a dimerization of two proteins, CLOCK and BMAL 1, driving transcription of the negative component of the feedback loop composed of dimerized of PER1 and CRY1. In the PT, rhythmic expression of Per1 occurs in the early light phase, peaking approximately 3 hr after lights on, with the amplitude reduced during SD exposure [19, 25–28]. Per1 is induced by cAMP and suppressed by acute melatonin treatment in ovine PT cell cultures, leading to the view that the morning induction of Per1 is because of the cessation of the melatonin signal allowing cAMP to rise. It is here where sensitization may play its role: owing to the inhibitory action of melatonin on cAMP generation, the induction of Per1 may be retarded in LD and SD, but in LD, activation of a Gs-protein-coupled receptor would enhance cAMP generation as a result of sensitization by melatonin, consequently elevating Per1 expression over SD values. The discovery of TSH synthesis [20, 29–32] and the presence of the TSH receptor on PT cells [20] provide a mechanism by which TSH, acting as a paracrine agent, may fulfil this role and provide an incremental positive feedback loop in the transition from SD to LD (Fig. 1).

Cry1, on the other hand, is induced at the onset of darkness, consistent with the ability of melatonin to promote the expression of this clock gene [21]. Consequently, as the interval of the light phase between dawn and dusk narrows in the transition between the summer and winter solstices, the time interval between the morning rise in Per1 and the evening rise in Cry1 in the PT is reduced. This potentially leads to a higher concentration of Per1/Cry1 inhibitory complexes. Conversely, in the transition from SD to LD, the time interval between the morning rise in Per1 and evening rise in Cry1 is lengthened lowering the potential of Per1/Cry1 complex formation. This pattern of induction has lead Lincoln and co-workers [27] to propose a coincidence model of Per1/Cry1 interaction leading to the seasonal output of the PT and downstream physiology.

Regulation of pars tuberalis TSHβ expression

Although inbred laboratory strains of mice have no known physiological responses to photoperiod, they can nevertheless respond to photoperiod via melatonin at the molecular level in the PT and in tanycytes lining the third ventricle [22, 32]. This response was utilized to investigate the interaction between melatonin receptors and clock components on TSHβ gene expression, a key output of the PT, to drive seasonal physiological responses in melatonin responsive C3H mice. In wild-type mice, the expression of TSHβ in the PT is low during the day and high at night. This diurnal pattern of expression is abolished in MT1 −/− null mice, where TSHβ expression is high and similar during the day and night. On the other hand, TSHβ expression in Per1 −/− null mice shows higher values during the day and lower levels during the night when melatonin would be present [22]. These data support a view that melatonin, via the MT1 receptor and Per1, interact and regulates TSHβ expression. Transcription factor binding site analysis of DNA sequence up to 3 kb from the coding sequence identifies 11 E-box elements and two cAMP response elements [22]. Luciferase reporter assays under the control of the TSHβ promoter region showed CLOCK and BMAL1 co-transfected with the reporter plasmid greatly enhanced TSHβ promoter-driven expression of the luciferase reporter [22]. However, as recent discoveries have uncovered more of the potential mechanism of TSHβ regulation, it remains to be resolved whether there is direct transcriptional activity of CLOCK and BMAL1 on TSHβ expression in vivo.

Using different approaches in two species, Dardente et al. [16] and Masumoto et al. [17] identified more of the basic mechanism by which TSHβ transcription is regulated by photoperiod. Several transcription factors or co-activators are involved, centred around binding of transcription factors thyrotroph embryonic factor (TEF) and hepatic leukaemia factor (HLF) to a D-box element in the promoter region for TSHβ.

A genome wide scan of PT tissue from LD- and SD-exposed mice identified transcriptional co-activators, Eya3 and Six1, showing similar temporal kinetics as TSH expression, both of which increase in LD. Within the mouse promoter, EYA3 and SIX1 acting together promote TSHβ transcription through binding to a So1-box located within the first 100 bp upstream of the transcriptional start site. TEF and HLF further enhance the transcription of TSHβ through binding to the D-box element located between the So1-box and the transcriptional start site [17].

Starting with a hypothesis that melatonin modulates TSH synthesis by regulating the expression or activity of transcription factors involved in circadian rhythms, Dardente et al. [16] found TEF and HLF binding to an upstream D-box element in the sheep TSHβ promoter region. Based on the studies in the quail and microarray studies in sheep PT tissue [15], EYA3 and SIX1 were also investigated as potential co-activators of transcription and revealed enhancement of TEF-mediated transcription of TSHβ. Thus, both studies point to Eya3 as one of the most important factors for regulating TSHβ expression. It is therefore important to understand how expression of Eya3 is itself regulated. Analysis of the upstream sequence of Eya3 identified three conserved E-boxes in the promoter and which Dardente et al. [16] suggest may be regulated by CLOCK and BMAL involving a positive feedback loop by TEF through a conserved upstream D-box element in the Eya3 promoter, but this has yet to be demonstrated experimentally.

Interestingly, the D-box element may hold the key to seasonal responsiveness among mammalian species. Dardente et al. [16] reveal that an alteration in the sequence of the D-box element of the TSH promoter has substantial effects on the ability of TEF to enhance transcription of TSHβ. They examined the D-box element from mice, humans, marmoset, pig and sheep. The mouse D-box element had the highest efficiency, and the pig had very poor efficiency to promote TSHβ transcription. Intriguingly, the D-box element of humans was approximately between these two extremes. This would suggest that if melatonin receptors are present on human PT tissue, interpretation of seasonal photoperiodicity may be a possibility. It will be interesting to carry out single nucleotide polymorphism analysis of individuals who suffer seasonal affective disorder to assess whether this could account for the susceptibility of some individuals, and not others, to the possible depressive effects of long winter nights.

Tanycytes – a portal between the pars tuberalis and the hypothalamus

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

Whilst the PT is the site of action for melatonin, several lines of evidence, including studies involving hypothalamic-pituitary disconnected sheep, support the view that seasonal body weight and reproductive axes are regulated centrally [33–35]. A major question is how and by what means does the PT communicate with the brain?

The possibility that tanycytes are involved in hypothalamic functions was the basis for investigations of these cells by a number of investigators in the 1960s and 70s; these cells exhibited alterations of morphology or chemical staining as a result of the photoperiod, stress and sexual activity [36]. Early work on tanycytes described them as a group of cells lining the lower third of the dorsal wall of the third ventricle and the floor of the infundibular recess [36, 37]. Cytological analysis showed morphology of tanycytes as nonciliated cells with long basal process extending to the basal lamina, terminating as endfeet that were in contact with fenestrated vessels of the portal plexus in the median eminence [38, 39] and, more recently, with fenestrated blood vessels that infiltrate the ventromedial arcuate nucleus (ARC) [40, 41].

Ultrastructural analysis of the mediobasal hypothalamus suggests tanycytic endfeet are important for regulating the access of neuronal axon terminals to fenestrated portal blood vessels. In particular, during the oestrous cycle of female rats, tanycyte endfeet are observed to be retracted during the oestrogen-induced preovulatory gonadotropin-releasing hormone (GnRH) surge facilitating access of GnRH neuronal terminals to fenestrated blood vessels [42].

In the seasonal context, plasticity has been demonstrated in two LD-breeding animals, the Siberian hamster and the Japanese quail. In the quail, tanycytic endfeet contact a larger surface area of the basal lamina in the external zone of the median eminence during SD exposure compared with LD exposure [43]. This conforms to a role for tanycytes in controlling the seasonal release of GnRH from axon terminals. However, in Siberian hamsters held in constant darkness for 1 month or exposed to SD for a period of 2 months, the reverse situation occurs with substantially reduced innervation and fewer contacts between tanycytes and axon terminals [44]. As a result, this does not support the notion for a function of tanycyte endfeet to solely impede release of GnRH. Thus, the response of tanycytic endfeet in the Siberian hamster would be expected to enhance GnRH release and promote reproductive physiology and behaviour. Therefore it is likely that the relationship between endfeet and release of hypophysiotrophic hormones is not a simple one and interactions between tanycyte endfeet and axon terminals containing other hypophysiotrophic hormones may be involved and have a bearing on the seasonal hypothalamic-pituitary axis.

Recently, Bolborea et al. [45] confirmed the observation of Kameda et al. [44] of SD-induced downregulation of the intermediate filament, vimentin, which may be involved in the alteration of tanycyte morphology. In addition, gene expression for neural cell adhesion molecule was also found to be downregulated in SD adding further support to structural plasticity of tanycytes with altered photoperiod. Importantly, both of these gene expression changes were shown to be effected by melatonin and independent of seasonal changes in sex steroids [45].

In addition to alterations in tanycyte morphology, many gene expression alterations have now been found to occur which are likely to contribute to the role tanycytes play in seasonal adaptations to physiology. Changes in expression of components of the thyroid hormone system are described later, but other changes include increase in expression of genes for glycogen and glucose metabolism, glutamine synthesis, lactate and glutamate transport [46]. These changes are proposed to have an involvement in modulating glutamate and neurotransmitter availability in the hypothalamic environment [46].

Tanycytes – a source of hypothalamic thyroid hormone

Studies in birds established an important role for thyroid hormones (T3 and T4) in seasonal reproductive rhythms [47–50], but only recently has the molecular basis for thyroid hormone action and a tangible connection between the PT and central mechanisms regulating seasonal physiology been established. Yoshimura et al. [51] using a subtractive hybridization approach discovered higher levels of type II deiodinase (Dio2) responsible for converting inactive T4 to active T3 (Fig. 2) in the hypothalamus of the Japanese quail in LD-exposed birds compared with those in SD [51]. In situ hybridization studies revealed the Dio2 expression occurred in tanycytes, suggesting tanycytes were the source of thyroid hormone. Subsequent studies found type III (Dio3) responsible for degrading T4 and T3 to inactive metabolites was expressed and reciprocally regulated by photoperiod in tanycytes of the quail [52], providing the basis for the measured lower T3 values in the hypothalamus of the quail in SD. Measurements of T3 and T4 in circulation showed no change between LD and SD photoperiod, providing evidence that local synthesis by tanycytes is the principal contributor to photoperiod-dependent hypothalamic T3 availability [51].

image

Figure 2.  A schematic representation of the relationship between the pars tuberalis (PT), the site of melatonin action, tanycytes, the intermediary relay station and neurons of the hypothalamus which govern centrally mediated mechanisms underlying body weight and reproduction. TSH produced and secreted by melatonin responsive cells of the PT gains access to tanycytes of the third ventricle. This may be via cisterns, bathed in cerebrospinal fluid which connect directly with the third ventricle; direct communication via tanycyte endfeet abutting PT cells or retrograde transport via the capillary network system that infiltrates the medial basal hypothalamus. The boxed diagram shows a schematic relationship between TSH action on tanycytes and deiodinase expression. TSH stimulates expression of type 2 deiodinase (Dio2) for T3 production and availability to the hypothalamus where this has consequences for neuronal interactions and expression of key components leading to the establishment of long-day physiology. A decline in short days of TSH originating from the PT leads to a reduction in Dio2 expression. This may account for some or all of the reduction in T3 availability to the hypothalamus (e.g. in the Syrian hamster). However, in some species (e.g. the Siberian hamster), a concurrent expression of type III (Dio3) may occur for the metabolism of T3 and T4 which will limit the availability of bioactive T3 to the hypothalamus in short days. It is not known whether the mechanism of induction of Dio3 expression involves a stimulatory receptor-mediated input (?) or whether it occurs by another mechanism as a result of a reduction in TSH input.

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Thyroidectomy and T4 replacement studies in sheep [53, 54] had previously demonstrated a central action of this thyroid hormone precursor for the spring termination of the breeding season in sheep, providing additional evidence for the involvement of the thyroid hormone system in the regulation of the seasonal reproductive physiology [55, 56]. Subsequently, led by the discoveries in the quail, regulation of Dio2 and Dio3 was found to occur in tanycytes of seasonal mammalian species, albeit with some variation in expression patterns. In the Syrian hamster (Mesocricetus auratus), for example, Dio2 is downregulated in SD and Dio3 does not appear to be expressed [57, 58]. In the Siberian hamster (Phodopus sungorus), Dio2 shows a partial downregulation by 8 wk of SD exposure, but then returns to full expression by 14 wk. Dio3, on the other hand, demonstrates interesting temporal kinetics, increasing in expression during the course of first 8 wk in SD, but declining thereafter [58]. In the European hamster (Cricetus cricetus) and Fischer F344 strain rats, Dio2 and Dio3 are reciprocally regulated [59–61]. Dio2 is also elevated in the tanycytes of sheep in LD [20], but at present, there is no information available as to the involvement of Dio3. Together, these data point to a local depletion of T3 as the trigger to induce seasonal changes in physiology. This view is supported by T4 microimplant studies in sheep [54] and T3 microimplant studies in Siberian hamsters [58]. In the latter, T3 microimplants into the hypothalamic region prevented the SD-induced reduction in body weight and testicular regression, but did not prevent the SD-mediated pelage moult, a response governed by a local PT–pituitary interaction [62].

In addition to the modulation of hypothalamic T3 availability via regulation of Dio2 and Dio3 expression, thyroid hormone transport may also be involved. MCT8, a specific thyroid hormone transporter [63], has been shown to be regulated by photoperiod in tanycytes of the Siberian hamster and F344 rat. But paradoxically, Mct8 shows increased expression in SD, a counter-intuitive response given that a reduction in hypothalamic T3 is required to drive the transition to SD physiology [60, 64]. The significance of this has yet to be determined, but given that Dio2 and Dio3 mRNAs exist within the same cells during the development of SD physiology, there is a possibility that a metabolite of T3 may be involved in the seasonal response. A more parsimonious explanation is that rT3, a product of Dio3 enzyme activity on T4, is required to inhibit Dio2 activity [65] as expression of Dio2 only partially decreases in the Siberian hamster.

Tanycytes of the F344 rat also show regulation of an alternative thyroid hormone transporter Oatp1c1, which is elevated in LD consistent with a role in increasing thyroid hormone supply [60]. Taken together, these data support the view that regulation of T3 availability to the hypothalamus is a key factor in driving seasonal physiological responses.

The link between melatonin action in the PT and regulation of deiodinase activity in tanycytes was discovered independently using two different approaches [20, 66]. Nakao et al. [66] used the advantage of the rapid response in LH secretion in the Japanese quail when switched from SD to LD with concomitant differential expression of Dio2 and Dio3. Application of a genome wide expression analysis to identify temporally regulated waves of gene expression in the mediobasal hypothalamus underpinning the photoresponsiveness of the quail revealed a first wave of gene expression following the switch from SD to LD which included an increase in expression of TSHβ. This was followed by a second wave of gene expression 4–5 h later, which included upregulation of Dio2 expression. Regulated expression of TSHβ was localized to the PT leading to a hypothesis that PT-derived TSH may be the signal for photoperiod-mediated changes in physiology. Subsequently, in situ hybridization analysis demonstrated TSH receptor gene expression in tanycytes and intracerebral ventricular injection of TSH led to an increase in genes known to be regulated by cAMP including Creb, Icer and Dio2 [66].

A similar conclusion was derived from studies in Soay sheep, based on previous observations of regulation of TSHβ and αGSU by photoperiod in the PT of the Siberian hamster [67]. Thus, in the Soay sheep, TSHβ is elevated in LD, TSH receptors are found both on cells of the ependymal layer (tanycytes) and on PT cells and TSH infused into the lateral ventricles induces Dio2 expression [20]. Together, these data imply tanycytes are a portal between melatonin action in the PT and a central response leading to physiological adaptations in body weight and the reproductive axis.

Recently, a detailed ultrastructural analysis of the rat PT has provided a new insight as to how the PT may communicate a TSH signal with tanycytes of the third ventricle. This study reveals a complex architecture of the PT consisting of secretory and nonsecretory cells surrounding a cavity (cistern) that is in open communication with the CSF allowing direct access of PT-secreted products access to tanycytes (Fig. 2) [68]. In addition, tanycytic process has been found to terminate on PT cells and thereby potentially facilitating direct communication between PT cells and tanycytes. Another potential route of access of TSH to tanycytes is release into the portal blood vessels with a retrograde blood flow to the hypothalamus. This concept is in opposition to the classical view of neuroendocrine communication between the hypothalamus and pituitary gland via anterograde flow of blood in the portal blood vessels leading from axon terminal of the median eminence to the pituitary gland. However, recent evidence supports the concept of retrograde blood flow to the basal ARC region of the hypothalamus [40], leaving open the potential for this route of communication between the PT and the brain.

Thyroid hormone replacement experiments performed in birds, sheep and Siberian hamster clearly show that thyroid hormone is an important agent for the translation of photoperiod. Furthermore, tanycytes are key cells in relaying the thyroid hormone to initiate the seasonal change in physiology. However, it should not be overlooked that tanycytes may have an important role in transport or responses to other biologically active or prohormone molecules. One strong candidate for which tanycytes may act as a gatekeeper is retinol. Studies on the Siberian hamster and rat have shown components of the retinoic acid signalling system to be present in tanycytes, including STRA6, CRBP1 (transport proteins for retinol), RADLH2 for the conversion of retinol to retinoic acid, and the receptor for retinoic acid, RAR. The expression of some of one or more of these components (CRBP1, RADLH2 and RAR) is downregulated in SD in tanycytes or hypothalamic structures in the Siberian hamster and the F344 rat, suggesting this signalling pathway is also important to hypothalamic responses underlying seasonal physiology [69–72].

The orphan G-protein-coupled receptor (GPR50) that shares significant homology with the melatonin receptor family, but does not bind melatonin [73–75], is highly expressed in tanycytes [76] and is downregulated in the SD-exposed Siberian hamster [71]. This would suggest that the ligand for GPR50 is important in mediating an endocrine, neuropeptide or neurotransmitter signalling to tanycytes of LD-exposed hamsters, but the precise role of this receptor and whether downregulation may be involved in alteration in tanycyte functions in SD will require further studies once the ligand has been identified or technological approaches used to carry out tanycyte knock-down or over-expression studies become available.

The mouse is generally not considered to be a seasonal mammal. This could be attributed to the use of mouse strains that do not synthesize melatonin; however, even in melatonin proficient mice, changes in seasonal physiology have not been noted. Nevertheless, as mentioned earlier, mice are responsive to photoperiod at the level of the PT and demonstrate photoperiod regulation of Dio2 expression at the level of the tanycyte [32]. This being the case, it suggests that as the molecular mechanisms exist within the PT and tanycytes are largely intact, the inability to respond to seasonal photoperiod lies downstream of the first two components required for the interpretation of photoperiod.

Beyond the tanycyte

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

Microimplant studies carried out in sheep and Siberian hamsters provide good evidence for the action of centrally mediated effects of thyroid hormone in mammals to effect seasonal physiology and behaviour. Although, the requirement of thyroid hormone is at contrasting points in the annual cycle, i.e., it is required for the termination of the breeding season in sheep [54], whilst it is required to maintain at least LD physiology in the Siberian hamster [58]. As a consequence, thyroid hormone receptors will be an essential component to convey the photoperiod-driven change in hypothalamic thyroid hormone availability. A detailed knowledge on the distribution of thyroid hormone receptors and their neuronal phenotype, however, is far from complete. Recent evidence suggests that TRα1, one of the four main thyroid hormone receptors, is ubiquitously expressed in all neurons of the brain and likewise also expressed in tanycytes [77]. The other principal thyroid hormone receptors, TRα2, TRβ1 and TRβ2, are localized in a number of hypothalamic structures [78]. In relation to seasonal species, currently, only data are available for the Siberian hamster. In this species, TRα1 has a widespread distribution, whilst TRβ1 and TRβ2 were found in similar hypothalamic areas including the ventral medial nucleus (VMN), ARC and dmpARC [58]. TRβ2 was also found in the premammillary area. In the Siberian hamster, TRβ1 was not regulated by photoperiod, but TRβ2 was increased by 40% in the hypothalamus of SD-exposed animals, including the dmpARC, but excluding the premammillay area.

The increase in hypothalamic TRβ2 expression in SD in the Siberian hamster could be due to a reduction in hypothalamic thyroid hormone levels. However, as thyroid hormone receptors may have a repressive action on transcriptional activity in the absence of thyroid hormone [79], the increase in TRβ2 convergent with reduced hypothalamic T3 levels may be part of a mechanism to further suppress T3-regulated genes in the dmpARC and elsewhere. The potential transcriptional targets of the thyroid hormone in the hypothalamus are not yet known and could vary with species. Although many of the gene expression changes seen in the hypothalamus of photoresponsive mammals could be as a direct action of thyroid hormone receptor activation or repression, it is more likely that only a few genes will be regulated by thyroid hormone and others likely change as a secondary consequence. Such examples include, hypothalamic Ghrh downregulation in SD-exposed F344 rat as a result of an increase in NPY in the ARC [80] and an increase in c-fos and Vgf expression in the dmpARC of SD-maintained Siberian hamsters. Both of these latter genes are activated by cAMP signalling and may increase as a consequence of a downregulation of cAMP inhibitory histamine H3 receptor [81, 82].

As mentioned earlier, thyroid hormone implant experiments provide evidence that this agent is the principal regulator of photoperiod regulated changes in seasonal physiology. Direct or indirect transcriptional activity of genes regulated by thyroid hormone will, therefore, be intimately involved in the regulation of seasonal physiology underpinning reproduction and energy balance.

Reproduction

Of the hypothalamic genes regulated by the seasonal variation in the duration of nocturnal melatonin, few appear to be directly linked to reproductive function exceptions being genes encoding peptides belonging to the RFamide family of peptides [83–85]. Of these, Kiss1 is a primary candidate for a role in seasonal reproductive activity.

Kiss1 encodes for a preproprotein of 145 amino acids that is cleaved into four different peptides ranging from 10 to 54 amino acids termed kisspeptins [86]. A clear difference among these peptides is not yet established, but all bind a G-protein-coupled receptor Kiss1R (also known as GPR54). In rodents, Kiss1 is expressed mainly in two hypothalamic nuclei, the anteroventral periventricular (AVPV) nucleus and the ARC [87–89]. The AVPV neurons are known to play a key role in the positive feedback of oestrogen leading to the preovulatory surge of luteinizing hormone (LH) [90–92]. Consistent with a role in reproduction, Kiss1 expression is strongly regulated by sex steroid levels, being stimulated in the AVPV (but inhibited in the ARC) in rodents and sheep [93–95]. Thus, Kiss1 neurons appear to be implicated in the relay of sex steroid feedback on the hypothalamus–pituitary–gonads axis.

In seasonal mammals, Kiss1 expression is sensitive to photoperiod changes, but contrasting data cloud the precise role of kisspeptins of AVPV and ARC origins. The Syrian hamster exhibits a reduction in Kiss1 expression in both the ARC and AVPV nuclei in SD. However, at these sites, experiments utilizing melatonin injection or pinealectomy indicate Kiss1 in the ARC is regulated by melatonin, whilst AVPV expression is likely to be regulated by sex steroid feedback [84, 88, 95, 96]. Consistent with the Syrian hamster, Kiss1 expression in the AVPV nuclei of the Siberian hamster is also decreased during SD exposure, but in contrast is increased in the ARC [96]. Thus, although kisspeptins are primary candidates for a role in seasonal reproduction, work is still required to resolve the origin of kisspeptins that affect GnRH release and whether Kiss1 is a primary or secondary target of thyroid hormone action.

Whilst kisspeptins provide the stimulatory component to the reproductive axis, the RFamide peptide family contains other peptides which also may provide a counterbalance. The RFamide-related peptide (RFRP) group of peptides are the product of the Rfrp gene which is expressed in the hypothalamus and regulated by the photoperiod [85]. The Rfrp gene is the mammalian orthologue of the avian gonadotropin inhibitory hormone (GnIH) and is known to have an inhibitory effect on the hypothalamus–pituitary–gonads axis not only in the quail, but also in rats and hamsters [85, 97, 98].

The Rfrp gene encodes for a preproprotein, which can be cleaved into two peptides in rodent species, (RFRP-1 and RFRP-3) that are found in the dorsomedial nucleus and the VMN of rats [99, 100]. RFRP-3 has been demonstrated to inhibit LH release in rats and Syrian hamsters an effect mediated via a central action of this peptide rather than effect on gonadotrope cells of the anterior pituitary gland [98].

In sheep, Rfrp gene expression is elevated in LD [101], consistent with a suppressive action on GnRH release but in both Syrian and Siberian hamsters, Rfrp gene expression is decreased in SD when these hamsters are reproductively quiescent. However, it has been observed that the fibre content of RFRP-3 peptide levels is elevated in SD, leading to the proposal that an increase in peptide release at the onset of SD exposure provides the drive to inhibit the reproductive axis [98].

Body weight regulation

The homeostasis of body weight regulation involves a balance between the orexigenic and anorexigenic signalling systems in the brain. A wealth of data has accumulated on the principal neuropeptides involved. Within the ARC, orexigenic peptides NPY and AGRP induce an increase in food intake and a reduction in energy expenditure while anorexigenic peptides, POMC and CART, have the opposite actions [102]. These neuropeptides have been investigated in the context of appetite and energy balance regulation of photo-responsive mammals. The F344 rat has been shown to respond to changing photoperiods with a reduced rate of growth and a reduction in food intake in SD [60, 80]. In this species, Npy expression in the ARC increases and Agrp decreases in SD. This divergent response of co-expressed orexigenic genes might be expected to negate the action of these peptides to elevate food intake on the one hand (increased NPY) and decrease food intake on the other (decreased AGRP). However, as the authors suggest, higher levels of NPY may serve a function that is parallel to the action of NPY in a fasted animal, which is one of suppressing the growth axis, while the decreased Agrp expression may facilitate increased signalling by the POMC-derived peptide, αMSH, to reduce food intake [80].

In other seasonal mammals, whilst genes for neuropeptides involved in energy balance homeostasis are perturbed by fasting, the involvement of these systems in seasonal body weight regulation is more equivocal. For example, in the Siberian hamster, there is no change in Npy, an increase in Agrp and drop in Pomc gene expression in SD [103, 104]. While in sheep, there are equivocal reports on the effect of photoperiod on Npy gene expression, in contrast to the Siberian hamster, Agrp is reduced and Pomc increased in SD. Cart shows a rise in the ARC in both the Siberian hamster and sheep [105–107], consistent with the potential role of CART as an anorexigenic peptide. In the Siberian hamster, CART gene expression has been reported to occur early (by 14 days) in SD [108]. As seasonal physiology depends upon a decrease in thyroid hormone levels, for the Siberian hamster at least, CART involvement in SD-induced weight loss is questionable. This is because Dio3 does not appreciably increase its expression for at least 4 wk after the onset of SD exposure [58]. Thus, unless there is a precipitous loss of Dio2 or another mechanism to substantially lower hypothalamic thyroid hormone, an early induction of Cart may not depend upon reduced thyroid hormone.

Intriguing data have recently emerged from a study on the Siberian hamster, suggesting a pathway by which seasonal mobilization of adipose tissue may be implemented [82]. In this species, histamine H3 receptors in the dmpARC suppress neuronal firing of the dmpARC neurons in LD. Under SD conditions, histamine H3 receptors are downregulated. As a result, neuronal firing rate is increased 4- to 5-fold. This increased activity is consistent with a constitutive expression of c-fos in dmpARC neurons indicative of elevated neuronal activation. Pseudorabies track-tracing studies revealed that dmpARC neurons are infected by the virus following its injection into inguinal fat pad tissue, documenting a sympathetic neural pathway between the dmpARC and adipose tissue. Therefore, increased neuron activity in SD may contribute to the mobilization of fat tissue in the hamster. Remarkably, the gene for the protein VGF has also increased the dmpARC. This large protein has been proposed to be a precursor of a number of biologically active peptides, one of which (TLQP-21) has been shown to inhibit food intake and reduce body weight in the Siberian hamster [109]. The histamine H3 receptor is an inhibitory receptor for the cAMP signalling pathway, and downregulation of this receptor may be the mechanism that facilitates increases in c-fos and VGF (both can be stimulated by a rise in cAMP). However, the link between hypothalamic T3 concentration and expression of the histamine H3 receptor is less clear and will require an analysis of the promoter region of this gene to determine whether regulation by T3 is direct or indirect.

The changes in gene expression of the dmpARC and at other hypothalamic sites in the hamster and other species will contribute to the formation of the central mechanisms involved in responding to environmental changes predicted by the annual cycle of photoperiod duration. However, further work is required to fully establish their contribution to body weight regulation or other aspects of seasonal physiology.

The evidence strongly indicates that the PT is the principal site for the translation of the annual daily variation in duration of pineal melatonin. The melatonin signal is translated to seasonal synthesis and secretion of TSH from the PT (high in summer, low or absent in winter) involving a mechanism using cAMP signalling and components of the molecular clock work. Tanycytes of the third ventricle appear to be the cellular link between the PT and neuronal responses leading to physiological adaptations in reproduction and body weight, wherein thyroid hormone synthesis governed by PT-derived TSH leads to hypothalamic regulation of seasonal physiology. Details of the mechanism from melatonin binding at receptors on the PT to the molecular changes in the PT cells that govern TSH synthesis and secretion are being unravelled, but our knowledge of this mechanism is still far from complete: for example, how does melatonin receptor activation lead to induction of Cry1 and how does the modulation of Per1 and Cry1 by melatonin feed through to regulation of TSH synthesis? In addition to TSH, are there any other factors secreted and governed by the melatonin signal, arising from the PT that may also be important to effect hypothalamic responses necessary for seasonal adaptations? Recent work has shown tanycytes of the third ventricle as a gateway linking the PT to neuronal responses, but we are only at an early stage in understanding the involvement of these cells. What is for example their relationship with the surrounding hypothalamic neurons where many of the photoperiod-driven changes take place? At the neuronal level, photoperiod-regulated gene expression changes in a number of hypothalamic nuclei have been identified, but the role of each of these genes and nuclei and their relationship to each other still remain to be determined. Furthermore are there other important genes involved in physiological responses to photoperiod yet to be discovered?

Finally, this review has focused on the communication pathway from the PT to the hypothalamus leading to regulation of body weight and reproduction. However, melatonin also governs seasonal pelage colour and quality through a PT–pituitary communication pathway. This has not been covered in this review but the reader is referred to a complimentary surrey covering this facet of the seasonal physiological response [110]. Also, other actions of melatonin at the level of the peripheral reproductive organs and on the associated secondary sexual organs are reviewed elsewhere [111].

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References

This work was supported by the Scottish Executive Environment and Rural Affairs Department, by the Biotechnology and Biological Sciences Research Council (UK) project grant BB/E020437/1. We would also like to thank Sandrine Dupre and Laura Ansel for critically reading the manuscript. Patricia Reid for illustrations.

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  2. Abstract
  3. Introduction
  4. The pars tuberalis
  5. Tanycytes – a portal between the pars tuberalis and the hypothalamus
  6. Beyond the tanycyte
  7. Acknowledgements
  8. References
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