Talk:Endocrine - Pineal Development

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Cite this page: Hill, M.A. (2021, April 23) Embryology Endocrine - Pineal Development. Retrieved from


Virtual discovery of melatonin receptor ligands to modulate circadian rhythms

melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light–dark cycle


Morphology and quantification of sheep pineal glands at pre-pubertal, pubertal and post-pubertal periods

Bolat D, Kürüm A & Canpolat S. (2018). Morphology and quantification of sheep pineal glands at pre-pubertal, pubertal and post-pubertal periods. Anat Histol Embryol , 47, 338-345. PMID: 29774950 DOI.

Bolat D1, Kürüm A2, Canpolat S3. Author information Abstract The pineal gland is a neuroendocrine organ associated with photoperiodic regulation in mammals. The aim of this study was to evaluate the pineal gland at the pre-pubertal, pubertal and post-pubertal periods by means of morphology and stereology. The study examined at total of 24 ovine pineal glands collected from healthy female Akkaraman breed. Thick sections (40 μm) were cut and treated with synaptophysin. Following each thick section, six consecutive sections at a thickness of 5 μm were cut. Each thin section was stained with one of the following dyes: Crossman's modified triple dye, glial fibrillary acidic protein (GFAP), melatonin marker, periodic acid-Schiff, Von Kossa and AgNOR. The pineal gland volume was measured using Cavalieri's method. The optical fractionator was used to estimate the total number of pinealocytes. The percentage of parenchyma and connective tissue and degree of vascularization were estimated by the area fraction fractionator method. The pineal gland volumes in the pre-pubertal, pubertal and post-pubertal groups were 7.53 ± 1.715 mm3 , 11.20 ± 1.336 mm3 and 17.75 ± 1.188 mm3 , respectively (p < .5). The number of pinealocytes in the pre-pubertal, pubertal and post-pubertal groups was 3,244,000 ± 228,076, 4,438,000 ± 243,610, 7,381,766 ± 406,223, respectively (p < .05). The glands of the post-pubertal group contained the highest amount of connective tissue (11.49 ± 2.103%; p < .5) and the largest GFAP staining area (p < .05). The melatonin staining density was the highest in the pubertal group. The density of lipofuscin staining was higher in the pubertal and post-pubertal groups. KEYWORDS: Cavalieri’s method; GFAP; area fraction fractionator; nucleator; optical fractionator; pineal gland PMID: 29774950 DOI: 10.1111/ahe.12359

Infradian Rhythm of the Content of Secretory Granules in Pinealocyte Cytoplasm in Mice and Rats

Gerasimov AV, Kostyuchenko VP, Potapov AV, Varakuta EY, Karpova MR, Sukhanova GA & Logvinov SV. (2018). Infradian Rhythm of the Content of Secretory Granules in Pinealocyte Cytoplasm in Mice and Rats. Bull. Exp. Biol. Med. , 165, 276-279. PMID: 29931631 DOI.

Bull Exp Biol Med. 2018 Jun;165(2):276-279. doi: 10.1007/s10517-018-4147-1. Epub 2018 Jun 21.

Gerasimov AV1, Kostyuchenko VP2, Potapov AV2, Varakuta EY2, Karpova MR2, Sukhanova GA2, Logvinov SV2. Author information Abstract The numerical density of secretory granules dense-core vesicles (DCV) in the cytoplasm of pinealocytes of the pineal gland was estimated by transmission electron microscopy in male white mice and Wistar rats. The 3-day biorhythm and lunaphase changes in the DCV content in the perikaryon and the processes of pinealocytes, which are manifested significantly in different seasons of the year, are established. The three-day biorhythm in adult male mice in comparison with younger male rats is not expressed uniformly in different phases of the moon. The in-phase manifestation of infradian biorhythms in different species of animals during the year with an unchanged daily photophase indicates the existence of common external synchronizers for mammals of these biorhythms that are not associated with the light/dark cycle. KEYWORDS: biorhythms; mammals; pineal gland; ultrastructuremetry PMID: 29931631 DOI: 10.1007/s10517-018-4147-1


Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator

PLoS One. 2016 Nov 18;11(11):e0167063. doi: 10.1371/journal.pone.0167063. eCollection 2016.

Ibañez Rodriguez MP1, Noctor SC2, Muñoz EM1.


The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. We applied systematic double, triple and quadruple labeling of cell-specific markers on prenatal, postnatal and mature rat pineal gland tissue combined with confocal microscopy to provide a comprehensive view of the cellular dynamics and cell lineages that contribute to pineal gland development. The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers.

PMID 27861587 PMCID: PMC5115862 DOI: 10.1371/journal.pone.0167063


The Lhx9 homeobox gene controls pineal gland development and prevents postnatal hydrocephalus

Brain Struct Funct. 2015 May;220(3):1497-509. doi: 10.1007/s00429-014-0740-x. Epub 2014 Mar 20.

Yamazaki F1, Møller M, Fu C, Clokie SJ, Zykovich A, Coon SL, Klein DC, Rath MF.


Lhx9 is a member of the LIM homeobox gene family. It is expressed during mammalian embryogenesis in the brain including the pineal gland. Deletion of Lhx9 results in sterility due to failure of gonadal development. The current study was initiated to investigate Lhx9 biology in the pineal gland. Lhx9 is highly expressed in the developing pineal gland of the rat with transcript abundance peaking early in development; transcript levels decrease postnatally to nearly undetectable levels in the adult, a temporal pattern that is generally similar to that reported for Lhx9 expression in other brain regions. Studies with C57BL/6J Lhx9 (-/-) mutant mice revealed marked alterations in brain and pineal development. Specifically, the superficial pineal gland is hypoplastic, being reduced to a small cluster of pinealocytes surrounded by meningeal and vascular tissue. The deep pineal gland and the pineal stalk are also reduced in size. Although the brains of neonatal Lhx9 (-/-) mutant mice appear normal, severe hydrocephalus develops in about 70 % of the Lhx9 (-/-) mice at 5-8 weeks of age; these observations are the first to document that deletion of Lhx9 results in hydrocephalus and as such indicate that Lhx9 contributes to the maintenance of normal brain structure. Whereas hydrocephalus is absent in neonatal Lhx9 (-/-)mutant mice, the neonatal pineal gland in these animals is hypoplastic. Accordingly, it appears that Lhx9 is essential for early development of the mammalian pineal gland and that this effect is not secondary to hydrocephalus.

PMID 24647753

Expression and cellular localization of the transcription factor NeuroD1 in the developing and adult rat pineal gland

J Pineal Res. 2015 May;58(4):439-51. doi: 10.1111/jpi.12228. Epub 2015 Mar 30.

Castro AE1, Benitez SG, Farias Altamirano LE, Savastano LE, Patterson SI, Muñoz EM.


Circadian rhythms govern many aspects of mammalian physiology. The daily pattern of melatonin synthesis and secretion is one of the classic examples of circadian oscillations. It is mediated by a class of neuroendocrine cells known as pinealocytes which are not yet fully defined. An established method to evaluate functional and cytological characters is through the expression of lineage-specific transcriptional regulators. NeuroD1 is a basic helix-loop-helix transcription factor involved in the specification and maintenance of both endocrine and neuronal phenotypes. We have previously described developmental and adult regulation of NeuroD1 mRNA in the rodent pineal gland. However, the transcript levels were not influenced by the elimination of sympathetic input, suggesting that any rhythmicity of NeuroD1 might be found downstream of transcription. Here, we describe NeuroD1 protein expression and cellular localization in the rat pineal gland during development and the daily cycle. In embryonic and perinatal stages, protein expression follows the mRNA pattern and is predominantly nuclear. Thereafter, NeuroD1 is mostly found in pinealocyte nuclei in the early part of the night and in cytoplasm during the day, a rhythm maintained into adulthood. Additionally, nocturnal nuclear NeuroD1 levels are reduced after sympathetic disruption, an effect mimicked by the in vivo administration of α- and β-adrenoceptor blockers. NeuroD1 phosphorylation at two sites, Ser(274) and Ser(336) , associates with nuclear localization in pinealocytes. These data suggest that NeuroD1 influences pineal phenotype both during development and adulthood, in an autonomic and phosphorylation-dependent manner. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. KEYWORDS: NeuroD1; nuclear-cytoplasmic partitioning; phosphorylation; pineal gland; post-translational modifications; serine residues

PMID 25752781


Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring

PLoS One. 2014 Mar 24;9(3):e91313. doi: 10.1371/journal.pone.0091313. eCollection 2014.

Vilches N1, Spichiger C1, Mendez N1, Abarzua-Catalan L1, Galdames HA1, Hazlerigg DG2, Richter HG1, Torres-Farfan C1.


Epidemiological and experimental evidence correlates adverse intrauterine conditions with the onset of disease later in life. For a fetus to achieve a successful transition to extrauterine life, a myriad of temporally integrated humoral/biophysical signals must be accurately provided by the mother. We and others have shown the existence of daily rhythms in the fetus, with peripheral clocks being entrained by maternal cues, such as transplacental melatonin signaling. Among developing tissues, the fetal hippocampus is a key structure for learning and memory processing that may be anticipated as a sensitive target of gestational chronodisruption. Here, we used pregnant rats exposed to constant light treated with or without melatonin as a model of gestational chronodisruption, to investigate effects on the putative fetal hippocampus clock, as well as on adult offspring's rhythms, endocrine and spatial memory outcomes. The hippocampus of fetuses gestated under light:dark photoperiod (12:12 LD) displayed daily oscillatory expression of the clock genes Bmal1 and Per2, clock-controlled genes Mtnr1b, Slc2a4, Nr3c1 and NMDA receptor subunits 1B-3A-3B. In contrast, in the hippocampus of fetuses gestated under constant light (LL), these oscillations were suppressed. In the adult LL offspring (reared in LD during postpartum), we observed complete lack of day/night differences in plasma melatonin and decreased day/night differences in plasma corticosterone. In the adult LL offspring, overall hippocampal day/night difference of gene expression was decreased, which was accompanied by a significant deficit of spatial memory. Notably, maternal melatonin replacement to dams subjected to gestational chronodisruption prevented the effects observed in both, LL fetuses and adult LL offspring. Collectively, the present data point to adverse effects of gestational chronodisruption on long-term cognitive function; raising challenging questions about the consequences of shift work during pregnancy. The present study also supports that developmental plasticity in response to photoperiodic cues may be modulated by maternal melatonin.

PMID 24663672

Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology

Hum Reprod Update. 2014 Mar-Apr;20(2):293-307. doi: 10.1093/humupd/dmt054. Epub 2013 Oct 16.

Reiter RJ1, Tan DX, Korkmaz A, Rosales-Corral SA.


BACKGROUND: Research within the last decade has shown melatonin to have previously-unsuspected beneficial actions on the peripheral reproductive organs. Likewise, numerous investigations have documented that stable circadian rhythms are also helpful in maintaining reproductive health. The relationship of melatonin and circadian rhythmicity to maternal and fetal health is summarized in this review.

METHODS: Databases were searched for the related published English literature up to 15 May 2013. The search terms used in various combinations included melatonin, circadian rhythms, biological clock, suprachiasmatic nucleus, ovary, pregnancy, uterus, placenta, fetus, pre-eclampsia, intrauterine growth restriction, ischemia-reperfusion, chronodisruption, antioxidants, oxidative stress and free radicals. The results of the studies uncovered are summarized herein.

RESULTS: Both melatonin and circadian rhythms impact reproduction, especially during pregnancy. Melatonin is a multifaceted molecule with direct free radical scavenging and indirect antioxidant activities. Melatonin is produced in both the ovary and in the placenta where it protects against molecular mutilation and cellular dysfunction arising from oxidative/nitrosative stress. The placenta, in particular, is often a site of excessive free radical generation due to less than optimal adhesion to the uterine wall, which leads to either persistent hypoxia or intermittent hypoxia and reoxygenation, processes that cause massive free radical generation and organ dysfunction. This may contribute to pre-eclampsia and other disorders which often complicate pregnancy. Melatonin has ameliorated free radical damage to the placenta and to the fetus in experiments using non-human mammals. Likewise, the maintenance of a regular maternal light/dark and sleep/wake cycle is important to stabilize circadian rhythms generated by the maternal central circadian pacemaker, the suprachiasmatic nuclei. Optimal circadian rhythmicity in the mother is important since her circadian clock, either directly or indirectly via the melatonin rhythm, programs the developing master oscillator of the fetus. Experimental studies have shown that disturbed maternal circadian rhythms, referred to as chronodisruption, and perturbed melatonin cycles have negative consequences for the maturing fetal oscillators, which may lead to psychological and behavioral problems in the newborn. To optimize regular circadian rhythms and prevent disturbances of the melatonin cycle during pregnancy, shift work and bright light exposure at night should be avoided, especially during the last trimester of pregnancy. Finally, melatonin synergizes with oxytocin to promote delivery of the fetus. Since blood melatonin levels are normally highest during the dark period, the propensity of childbirth to occur at night may relate to the high levels of melatonin at this time which work in concert with oxytocin to enhance the strength of uterine contractions.

CONCLUSIONS: A number of conclusions naturally evolve from the data summarized in this review: (i) melatonin, of both pineal and placental origin, has essential functions in fetal maturation and placenta/uterine homeostasis; (ii) circadian clock genes, which are components of all cells including those in the peripheral reproductive organs, have important roles in reproductive and organismal (fetal and maternal) physiology; (iii) due to the potent antioxidant actions of melatonin, coupled with its virtual absence of toxicity, this indoleamine may have utility in the treatment of pre-eclampsia, intrauterine growth restriction, placental and fetal ischemia/reperfusion, etc. (iv) the propensity for parturition to occur at night may relate to the synergism between the nocturnal increase in melatonin and oxytocin. KEYWORDS: circadian rhythms, fetus, melatonin, placenta, pre-eclampsia

PMID 24132226

Extracellular matrix components mark the territories of circumventricular organs

Neurosci Lett. 2014 Apr 30;566:36-41. doi: 10.1016/j.neulet.2014.02.016. Epub 2014 Feb 20.

Pócsai K1, Kálmán M2.


In the central nervous system the extracellular matrix has important roles, e.g. supporting the extracellular space, controlling the tissue hydration, binding soluble factors and influencing their diffusion. The distribution of the extracellular matrix components in the brain has been mapped but data on the circumventricular organs (CVOs) is not available yet. The CVOs lack the blood-brain barrier and have relatively large perivascular spaces. The present study investigates tenascin-R and the lecticans: aggrecan, brevican, neurocan, and versican in the median eminence, the area postrema, the vascular organ of the lamina terminalis, the subfornical organ, the pineal body and the subcommissural organ of the rat applying immunohistochemical methods, and lectin histochemistry, using Wisteria floribunda agglutinin (WFA). The extracellular matrix components were found intensely expressed in the CVOs with two exceptions: aggrecan immunoreactivity visualized only neurons in the arcuate nucleus, and the subcommissural organ was not labeled with either WFA, or lecticans, or tenascin-R. The different labelings usually overlapped each other. The distribution of the extracellular matrix components marked the territories of the CVOs. Considering these we suppose that the extracellular matrix is essential in the maintenance of CVO functions providing the large extracellular space which is required for diffusion and other processes important in their chemosensitive and neurosecretory activities. The decrease of extracellular matrix beyond the border of the organs may contribute to the control of the diffusion of molecules from the CVOs into the surrounding brain substance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved. KEYWORDS: Area postrema, Lectican, Median eminence, Subfornical organ, Tenascin, Wisteria floribunda agglutinin

PMID 24561092

Mediator subunit 12 coordinates intrinsic and extrinsic control of epithalamic development

Dev Biol. 2014 Jan 1;385(1):13-22. doi: 10.1016/j.ydbio.2013.10.023. Epub 2013 Oct 30.

Wu SY1, de Borsetti NH, Bain EJ, Bulow CR, Gamse JT.


In the developing brain, the production of neurons from multipotent precursors must be carefully regulated in order to generate the appropriate numbers of various differentiated neuronal types. Inductive signals from extrinsic elements such as growth factors need to be integrated with timely expression of intrinsic elements such as transcription factors that define the competence of the cell. The transcriptional Mediator complex offers a mechanism to coordinate the timing and levels of intrinsic and extrinsic influences by acting as a rapid molecular switch for transcription of poised RNA pol II. The epithalamus is a highly conserved region of the vertebrate brain that differentiates early and rapidly in the zebrafish. It includes the pineal and parapineal organs and the habenular nuclei. Mutation of the Mediator complex subunit Med12 impairs the specification of habenular and parapineal neurons and causes a loss of differentiation in pineal neurons and photoreceptors. Although FGF ligands and transcription factors for parapineal and photoreceptor development are still expressed in the pineal complex of med12 mutants, FGF signaling is impaired and transcription factor expression is reduced and/or delayed. We find that the timely expression of one of these transcription factors, tbx2b, is controlled by Med12 and is vital for parapineal specification. We propose that the Mediator complex is responsible for subtle but significant changes in transcriptional timing and amplitude that are essential for coordinating the development of neurons in the epithalamus. © 2013 Published by Elsevier Inc. KEYWORDS: Epithalamus, Med12, Parapineal organ, Transcriptional regulation

PMID 24184636


Fgf signaling governs cell fate in the zebrafish pineal complex

Development. 2013 Jan;140(2):323-32. doi: 10.1242/dev.083709. Clanton JA, Hope KD, Gamse JT.


Department of Biological Sciences, Vanderbilt University, Nashville, TN 37205, USA. Abstract Left-right (L-R) asymmetries in neuroanatomy exist throughout the animal kingdom, with implications for function and behavior. The molecular mechanisms that control formation of such asymmetries are beginning to be understood. Significant progress has been made by studying the zebrafish parapineal organ, a group of neurons on the left side of the epithalamus. Parapineal cells arise from the medially located pineal complex anlage and migrate to the left side of the brain. We have found that Fgf8a regulates a fate decision among anterior pineal complex progenitors that occurs just prior to the initiation of leftward migration. Cell fate analysis shows that in the absence of Fgf8a a subset of cells in the anterior pineal complex anlage differentiate as cone photoreceptors rather than parapineal neurons. Fgf8a acts permissively to promote parapineal fate in conjunction with the transcription factor Tbx2b, but might also block cone photoreceptor fate. We conclude that this subset of anterior pineal complex precursors, which normally become parapineal cells, are bipotential and require Fgf8a to maintain parapineal identity and/or prevent cone identity.

PMID 23250206

The role of melatonin as an antioxidant in the follicle

J Ovarian Res. 2012 Jan 26;5:5.

Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N. Source Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube, 755-8505 Japan.


ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.

PMID 22277103


Masses and malformations of the third ventricle: normal anatomic relationships and differential diagnoses

Radiographics. 2011 Nov-Dec;31(7):1889-905. doi: 10.1148/rg.317115083.

Glastonbury CM, Osborn AG, Salzman KL. Source Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Ave, Box 0628, Room L-358, San Francisco, CA 94143-0628, USA. Abstract The third ventricle lies in the center of the brain. It is surrounded by critical nuclear structures (the hypothalamus and thalami) and important glandular structures (the pituitary and pineal glands). Although a wide array of pathologic processes may involve the third ventricle, most are extrinsic masses. By understanding the anatomic boundaries of the third ventricle and its relationship to adjacent structures, it is possible to create short lists of differential diagnoses. Third ventricle masses can be classified as arising in or immediately adjacent to one of five locations: anterior, posterior, inferior, foramen of Monro, and intraventricular. Anterior masses involve the optic and infundibular recesses, posterior masses affect or arise in the posterior commissure and pineal gland, and inferior masses involve or affect the ventricle floor. Masses may also arise at or adjacent to the foramen of Monro or entirely within the third ventricle. Of the intraventricular masses, chordoid glioma-a rare low-grade primary neoplasm-is unique to the third ventricle. Congenital malformations of the third ventricle are uncommon and are most often noted during childhood. Most commonly, these anomalies represent malformations of the neurohypophysis, which may manifest as hormonal abnormalities, or stenosis of the aqueduct of Sylvius, which manifests as dilatation of the third and lateral ventricles (hydrocephalus).

PMID 22084178

Melatonin as a central molecule connecting neural development and calcium signaling

Funct Integr Genomics. 2011 Apr 5. [Epub ahead of print]

de Faria Poloni J, Feltes BC, Bonatto D. Source Instituto de Biotecnologia, Universidade de Caxias do Sul (UCS), Caxias do Sul, Rio Grande do Sul, Brazil.


Melatonin (MEL) is a neuroendocrine hormone secreted by the pineal gland in association with the suprachiasmatic nucleus and peripheral tissues. MEL has been observed to play a critical role in the reproductive process and in the fetomaternal interface. Extrapineal synthesis has been reported in mammalian models during pregnancy, especially by the placenta tissue. MEL can regulate intracellular processes (e.g., G-proteins) and the activity of second messengers (e.g., cAMP, IP(3,) Ca(2+)). During neurodevelopment, these activities regulated by melatonin have an important role as an intracellular signaling for gene expression regulation. To review the role of MEL in neurodevelopment, we built interactome networks of different proteins that act in these processes using systems biology tools. The analyses of interactome networks revealed that MEL could modulate neurodevelopment through the regulation of Ca(2+) intracellular levels and influencing BMP/SMAD signaling, thus affecting neural gene responses and neuronal differentiation.

PMID: 21465271


Tbx2b is required for the development of the parapineal organ

Development. 2008 May;135(9):1693-702. Epub 2008 Apr 2.

Snelson CD, Santhakumar K, Halpern ME, Gamse JT. Source Department of Biological Sciences, Vanderbilt University, VU Station B, Box 35-1634, Nashville, TN 37235, USA.


Structural differences between the left and right sides of the brain exist throughout the vertebrate lineage. By studying the zebrafish pineal complex, which exhibits notable asymmetries, both the genes and the cell movements that result in left-right differences can be characterized. The pineal complex consists of the midline pineal organ and the left-sided parapineal organ. The parapineal is responsible for instructing the asymmetric architecture of the bilateral habenulae, the brain nuclei that flank the pineal complex. Using in vivo time-lapse confocal microscopy, we find that the cells that form the parapineal organ migrate as a cluster of cells from the pineal complex anlage to the left side of the brain. In a screen for mutations that disrupted brain laterality, we identified a nonsense mutation in the T-box2b (tbx2b) gene, which encodes a transcription factor expressed in the pineal complex anlage. The tbx2b mutant makes fewer parapineal cells, and they remain as individuals near the midline rather than migrating leftward as a group. The reduced number and incorrect placement of parapineal cells result in symmetric development of the adjacent habenular nuclei. We conclude that tbx2b functions to specify the correct number of parapineal cells and to regulate their asymmetric migration.

PMID: 18385257


The pinealocytes of the human pineal gland: A light and electron microscopic study

Folia Morphol (Warsz). 2006 Aug;65(3):181-7. Al-Hussain SM1.

Abstract The pinealocytes of the pineal gland of children and adults were studied at both light and electron microscopic levels. The pinealocytes were classified into light and dark pinealocytes on the basis of their shape, nuclear infolding, cytoplasmic contents and staining density. The light pinealocytes outnumber the dark pinealocytes and both of them have thin processes. The light pinealocytes have round or oval cell bodies and nuclei and have vesicles and ribbons. The dark pinealocytes showed more variations in their shape. The nuclear membrane of the dark cells showed numerous infoldings with deep invagination of parts of the cytoplasm within the nuclear folds, giving the appearance of nuclear pellets. The dark pinealocytes contain pigment in their cytoplasm. In addition to the light and dark pinealocytes a very small cell type with an extremely thin and elongated cell body and nucleus was found. The cells of this type were almost always associated with vacuoles filled with flocculent material and accumulations of presumptive secretion in the extracellular compartment. The findings of this study were discussed in the light of the published data about the pinealocytes of human and non-human species. PMID 16988913


Induction of photosensitivity in neonatal rat pineal gland

Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11540-4.

Tosini G, Doyle S, Geusz M, Menaker M. Source Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW, Atlanta, GA 30310, USA.


Pineal glands removed from neonatal rats at 5, 7, and 9 days of age and explanted into short-term culture, synthesized melatonin when stimulated with norepinephrine (NE); their melatonin synthesis could not be suppressed with bright white light. Dispersed pineal cell cultures or pineal explants prepared from 1-day-old neonates and held in culture for 7 or 9 days also synthesized melatonin when stimulated with NE, but in these cases melatonin synthesis was significantly suppressed by light, demonstrating that the pineals had become photosensitive while in culture. The development of photosensitivity in culture could be partially or completely abolished by the continuous presence of 1 or 10 microm of NE in the culture medium. The pineals of all nonmammalian vertebrates are photoreceptive, whereas those of mammals do not normally respond to light. We hypothesize that a mechanism to suppress pineal photosensitivity by using NE released from sympathetic nerve endings evolved early in the history of mammals.

PMID 11005846


The role of melatonin in the human fetus (review)

Int J Mol Med. 1998 Mar;1(3):539-43.

Thomas L1, Drew JE, Abramovich DR, Williams LM.


Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable.

PMID 9852259


Factors influencing the development of melatonin rhythmicity in humans

J Clin Endocrinol Metab. 1996 Apr;81(4):1525-32.

Kennaway DJ, Goble FC, Stamp GE. Source Department of Obstetrics and Gynecology, University of Adelaide, Australia.


The emergence of melatonin rhythmicity was studied in 163 infants between 46-55 weeks postconception by monitoring the excretion of the urinary melatonin metabolite 6-sulfatoxymelatonin (aMT.6S). From this population, we examined the effects of gender, season, multiple birth, home birth, previous sudden infant death syndrome in the family, premature labor, spontaneous rupture of membranes, preeclampsia, intrauterine growth restriction, and nursery lighting on pineal rhythmicity. As previously reported, rhythmic excretion of aMT.6S appeared between 49-55 weeks postconception (9-15 weeks of age) in singleton babies born at term in the hospital. Full-term infants who had a sibling die of sudden infant death syndrome had a pattern of melatonin rhythm development no different from that of the control full-term infants. In contrast, full-term infants born at home and full-term twins born in the hospital had significantly lower aMT.6S excretion than hospital-born singleton infants at the same ages despite similar body weights (e.g. at 52 weeks postconception; 1.8 +/- 0.4, 1.1 +/- 0.3, and 3.6 +/ -0.5 nmol/day, respectively). In full-term infants, there was no difference in the development of melatonin rhythmicity between the sexes, with season or method of delivery (vaginal vs. caesarean). The premature infants were divided into 5 groups (babies born after premature labor, premature rupture of membranes, preeclampsia, intrauterine growth restriction, and fetal distress). All premature infants had a delay in the appearance of aMT.6S rhythms in the urine in relation to chronological age. When the infants were compared on the basis of weeks since conception, those infants born after spontaneous premature labor excreted amounts of aMT.6S no different from those of full-term singleton infants during the period of study. In contrast, the premature rupture of membranes, preeclampsia, and fetal distressed infants excreted 50% less aMT.6S, and intrauterine growth restricted infants excreted 67% less at the same postconceptional ages. These differences were due to reduced nocturnal excretion of the metabolite. In an attempt to accelerate the development of melatonin rhythmicity, premature labor and premature rupture of membranes infants were randomly assigned to be totally deprived of light (using phototherapy eye shields) or partially deprived of light by moving them to a dimly lit room each night for the last 3-8 weeks of their stay in the hospital nursery. Babies born after premature labor produced normal amounts of aMT.6S between 46-52 weeks postconception, and this pattern was not affected by the nocturnal light deprivation. Infants born after premature rupture of membranes and totally deprived of light at night had aMT.6S excretion rhythms at 52 weeks postconception no different from those of full-term hospital-born infants or premature labor infants, whereas those in infants placed in dim light were similar to those in untreated premature rupture of membranes infants. These results suggest that premature birth alone is not the sole cause of altered rhythm development; other factors, such as preeclampsia, growth restriction, and nursery lighting, play an important role. The consequences of the delayed appearance of melatonin in infants are not known, but deserve further study.

PMID: 8636362


The pineal gland: a comparative MR imaging study in children and adults with respect to normal anatomical variations and pineal cysts

Pediatr Radiol. 1995;25(4):245-8.

Sener RN. Source Department of Radiology, Ege University Hospital, Bornova, Izmir, Turkey.


This study was undertaken to evaluate the variations in appearance of the normal pineal gland. The findings of 1000 consecutive MR imaging examinations obtained at 0.5 T were studied. The age of the patients ranged from 1 day to 83 years, and findings in children and adults were compared. In all age groups the pineal gland appeared mainly in three forms: (1) nodule-like, (2) crescent-like and (3) ring-like. Overall prevalences of these forms were 52%, 26% and 22%, respectively. Apparent differences in frequencies were evident in children and adults with respect to the crescent- and ring-like types. Cystiform pineal lesions 5 mm or larger in one diameter (anteroposterior, sagittal or transverse) were taken to be true pineal cysts, when compared with the gland's ring-like appearance (less than 5 mm). Pineal cysts had a prevalence of 0.6% in children and 2.6% in adults. No symptomatic pineal cyst with mass effect on the lamina tecti was detected in the series. Besides identifying the three anatomical types of the pineal gland as seen on MR imaging and addressing the potential significance of differences in their frequencies in children and adults, the author tries to explain the previous discrepancy between the MR imaging and autopsy series findings with respect to frequencies of the pineal cysts.

PMID 7567225


The role of melatonin in the human fetus (review)

Int J Mol Med. 1998 Mar;1(3):539-43.

Thomas L1, Drew JE, Abramovich DR, Williams LM.


Melatonin, an indole amine, primarily derived from the pineal gland is secreted during the hours of darkness. Melatonin acts as a hormonal transduction of photoperiod influencing the timing of seasonal and daily (circadian) physiological rhythms. Maternal melatonin crosses the placenta and enters the fetal circulation providing photoperiodic information to the fetus influencing the subsequent circadian and seasonal rhythms of the offspring. The function of melatonin in humans is more obscure. However, melatonin has attained prominence as a treatment for disturbed circadian rhythms and sleep patterns which occur as a result of transmeridian travel, shift work or blindness. The biological clock, the hypothalamic suprachiasmatic nuclei (SCN), possesses melatonin receptors, in both the adult and fetal human. This concurs with the reported influence of melatonin on human circadian rhythmicity and indicates that this influence may begin in utero. Melatonin receptors are widespread in the human fetus and occur in both central and peripheral tissue from early in fetal development. Thus, the influence of melatonin on the developing human fetus may not be limited to entraining circadian rhythmicity. Considering the transplacental availability of melatonin to the fetus the ingestion of melatonin by pregnant women may be inadvisable. PMID: 9852259 [Indexed for MEDLINE]


Fine structure of the pinealopetal innervation of the mammalian pineal gland

Microsc Res Tech. 1992 May 1;21(3):188-204.

Møller M. Source Department B, University of Copenhagen, Denmark.


The mammalian pineal gland is innervated by peripheral sympathetic and parasympathetic nerve fibers as well as by nerve fibers originating in the central nervous system (central innervation). The perikarya of the sympathetic fibers are located in the superior cervical ganglia, while the fibers terminate in boutons containing small granular vesicles and a few large granular vesicles. Both noradrenaline and neuropeptide Y are contained in these neurons. The parasympathetic fibers originate from perikarya in the pterygopalatine ganglia. The neuropeptides, vasoactive intestinal peptide and peptide histidine isoleucine, are present in these fibers, the boutons of which contain small clear transmitter vesicles and larger granular vesicles. The fibers of the central innervation originate predominantly from perikarya located in hypothalamic and limbic forebrain structures as well as from perikarya in the optic system. These fibers terminate in boutons containing small clear and, in certain fibers, an abundant number of large granular vesicles. In rodents, the majority of the central fibers terminate in the deep pineal gland and the pineal stalk. From these areas impulses might be transmitted further caudally to the superficial pineal gland via neuronal structures or processes from pinealocytes. Several hypothalamic neuropeptides and monoamines might be contained in the central fibers. The intrapineal nerve fibers are located both in the perivascular spaces and intraparenchymally. The majority of the intraparenchymally located fibers terminate freely between the pinealocytes. However, some nerve terminals make synaptic contacts with the pinealocytes and in some species with intrapineal neurons. In fetal mammals, sympathetic, parasympathetic, and central fibers are also present. In addition, an unpaired nerve, connecting the caudal part of the pineal gland with the extreme rostral part of the mesencephalon, is present. This nerve is a homologue to the pineal nerve (nervus pinealis) observed in lower vertebrates.

PMID 1606315