Seasonal Reproduction in Vertebrates: Melatonin Synthesis, Binding, and Functionality Using Tinbergen’S Four Questions
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molecules Review Seasonal Reproduction in Vertebrates: Melatonin Synthesis, Binding, and Functionality Using Tinbergen’s Four Questions Dax viviD * and George E. Bentley Berkeley Department of Integrative Biology, University of California, Berkeley, CA 94720, USA; [email protected] * Correspondence: [email protected] Received: 22 December 2017; Accepted: 13 February 2018; Published: 13 March 2018 Abstract: One of the many functions of melatonin in vertebrates is seasonal reproductive timing. Longer nights in winter correspond to an extended duration of melatonin secretion. The purpose of this review is to discuss melatonin synthesis, receptor subtypes, and function in the context of seasonality across vertebrates. We conclude with Tinbergen’s Four Questions to create a comparative framework for future melatonin research in the context of seasonal reproduction. Keywords: melatonin; seasonal reproduction; vertebrates 1. Introduction “We begin in the dark, and birth is the death of us.” Antigon¯´e, Translated by Anne Carson The connection between darkness and birth is inextricable for photoperiodic, seasonally breeding animals. The tilt and rotation of the Earth creates geographical variation in temperature and daylength. Daily and annual fluctuations of environmental conditions outside of the tropics, resulting from these astronomical circumstances, correspond to changes in relative resource abundance. Organisms that detect light with the physiological mechanisms to track and store photic information over time can use daylength to anticipate environmental changes, subsequently altering behavior and physiology to optimize metabolism and seasonal reproductive timing. The synthesis of N-acetyl-5-methoxytryptamine, or melatonin, corresponds with darkness, thereby transducing photic information at the physiological level. The focus of this review is to overview melatonin research in the context of seasonal reproduction in photoperiodic breeding mammals, birds, and other vertebrates. Melatonin synthesis, binding, and signalling in the hypothalamo-pituitary gonadal (HPG) axis is discussed within existing models for molecular regulation of seasonal reproduction. We conclude by using the framework set forth by Tinbergen (1963) for ethology to pose questions to guide future experiments studying the connection between melatonin and seasonal reproduction. 2. Melatonin Synthesis Melatonin synthesis originated in mitochondria and chloroplasts [1]. The antioxidant cascade of byproducts in the biosynthetic pathway are speculated to serve a key role in evolutionary history. Derived from the amino acid tryptophan, melatonin is synthesized with four key enzymes. Enzymes in the biosynthetic pathway optimized functionality by peaking expression during the time of day with lower temperatures and UV radiation: nighttime. The main source of circulating melatonin in vertebrates is the pineal, and photic information, transmitted via the phototransduction pathway, is the primary regulator of pineal melatonin synthesis and secretion [2]. Molecules 2018, 23, 652; doi:10.3390/molecules23030652 www.mdpi.com/journal/molecules Molecules 2018, 23, 652 2 of 53 Molecules 2018, 23, x 2 of 51 2.1. Phototransduction Pathways in Mammals and Birds 2.1. Phototransduction Pathways in Mammals and Birds MelatoninMelatonin is is an an established established chemical chemical transducer transducer ofof photicphotic information because because its its synthesis synthesis in in photoreceptivephotoreceptive organisms organisms reaches reaches its it zeniths zenith in in darkness. darkness. The inverse relationship relationship between between day day length length andand the the length length of of the the subjective subjective night, night, which which variesvaries dependingdepending on on the the season season outside outside of of the the tropics, tropics, is translatedis translated through through the durationthe duration of melatonin of melatonin synthesis synthesis at night. at Thenight. duration The duration of melatonin of melatonin synthesis drivessynthesis the reproductive drives the reproductive state in a number state in of seasonal,a number photoperiodicof seasonal, photop breedingeriodic mammals. breeding Among mammals. these mammals,Among these there mammals, are short-day there breeders are short-day that breed breeders in winter that breed (e.g., in sheep) winter and(e.g., long-day sheep) and breeders long-day that breedbreeders in summer that breed (e.g., in hamsters). summer (e.g., The hamsters). gestation lengthsThe gestation vary tolengths enable vary parturition to enable at parturition the predicted at timethe of predicted year with time highest of resourceyear with abundance, highest resour springtime.ce abundance, Long winterspringtime nights,. Long corresponding winter nights, to an extendedcorresponding duration to of an melatonin extended synthesis,duration of stimulate melatoni then synthesis, reproductive stimulate axis ofthe short-day reproductive breeders axis andof inhibitshort-day long-day breeders breeders. and inhibit In hamsters, long-day a long-daybreeders. In breeder, hamsters, induced a long-day testicular breeder, regression induced observed testicular in extendedregression darkness observed can in be extended prevented darkness by removing can be prevented the pineal by gland removing or through the pineal bilateral gland or enucleation, through illustratingbilateral enucleation, the role light illustrating plays in reproductive the role light plays state [in3]. reproductive Pinealectomies state remove [3]. Pinealectomies a significant remove portion of circulatinga significant melatonin portion of acrosscirculating vertebrates melatonin [4 ],across and thevertebrates pineal gland [4], and continues the pineal to gland be researched continues asto a keybe component researched ofas a the key pathway component (see of Figure the pathway1) for photic(see Figure and 1) endogenous for photic and regulation endogenous of mammalian regulation melatoninof mammalian synthesis melatoni [5,6]. n synthesis [5,6]. FigureFigure 1. Phototransduction1. Phototransduction pathway pathway in in mammals. mammals. LightLight is detected by by the the retina. retina. Photic Photic information information is transducedis transduced via via the the retinohypothalamic retinohypothalamic tract tract to to nuclei nuclei inin thethe hypothalamus.hypothalamus. The The suprachiasmatic suprachiasmatic nucleusnucleus (SCN) (SCN) projects projects to to the the paraventricular paraventricular nucleus nucleus (PVN),(PVN), which synapses synapses in in the the superior superior cervical cervical ganglionganglion (SCG). (SCG). The The signal signal is is transmitted transmitted from from the theSCG SCG toto thethe Pineal.Pineal. Even in the wild, the impacts of artificial light at night suppresses melatonin levels and affect reproductiveEven in the physiology wild, the impacts in the tammer of artificial wallaby light at(Macropus night suppresses eugenii) [7] melatonin and European levels starlings and affect reproductive(Sturnus vulgari physiologys) [8], indicating in the there tammer are ecological wallaby (implicationsMacropus eugenii of the )[effects7] and of light European and melatonin starlings (Sturnuson mammalian vulgaris)[ and8], indicatingavian breeding there cycles. are ecological However, implications phototransduction of the effects in birds of includes light and pineal melatonin and ondeep-brain mammalian photoreceptors and avian breeding situated cycles. beneath However, a translucent phototransduction skull, whereas in in birds mammals includes photic pineal andinformation deep-brain is photoreceptors transduced via situated the retino-hypothalamic beneath a translucent pathway. skull, whereasBenoît conducted in mammals several photic informationexperiments is transduced in ducks via(Anas the platyrhynchos retino-hypothalamic) demonstrating pathway. that Benoît deep conducted brain photoreception several experiments was in duckssufficient (Anas to induce platyrhynchos testicular) demonstrating development if that the light deep administered brain photoreception includes blue was wavelengths sufficient to [9,10]. induce testicularBilateral development enucleation ifand the pinealectomy light administered in tree includes sparrows blue (Spizella wavelengths arborea) [did9,10 not]. Bilateral prevent enucleationtesticular andgrowth pinealectomy on long indays tree [11]. sparrows Although (Spizella this arboreastudy re) didmoves not the prevent main testicularsources of growth circulating on long melatonin, days [11 ]. Althoughdetectable this levels study of removes melatonin the has main been sources measured of circulating in plasma melatonin, after removal detectable of the eyes levels and of pineal melatonin in hasquail been (Coturnix measured japonica in plasma). One-third after ofremoval quail without of the these eyes photor andeceptive pineal inorgans quail could (Coturnix still entrain japonica to ). Molecules 2018, 23, 652 3 of 53 Molecules 2018, 23, x 3 of 51 One-third of quail without these photoreceptive organs could still entrain to a light-dark cycle [12]. a light-dark cycle [12]. These findings imply that melatonin synthesis occurs in yet another These findings imply that melatonin synthesis occurs in yet another photoreceptive site in birds. Given photoreceptive site in birds. Given that the other photoreceptive sites of birds, the eyes and pineal, that the other photoreceptive sites of birds, the eyes and pineal, use melatonin to transduce