RESUMO
The neurocranium is an integral part of the vertebrate head, itself a major evolutionary innovation1,2. However, its early history remains poorly understood, with great dissimilarity in form between the two living vertebrate groups: gnathostomes (jawed vertebrates) and cyclostomes (hagfishes and lampreys)2,3. The 100 Myr gap separating the Cambrian appearance of vertebrates4-6 from the earliest three-dimensionally preserved vertebrate neurocrania7 further obscures the origins of modern states. Here we use computed tomography to describe the cranial anatomy of an Ordovician stem-group gnathostome: Eriptychius americanus from the Harding Sandstone of Colorado, USA8. A fossilized head of Eriptychius preserves a symmetrical set of cartilages that we interpret as the preorbital neurocranium, enclosing the fronts of laterally placed orbits, terminally located mouth, olfactory bulbs and pineal organ. This suggests that, in the earliest gnathostomes, the neurocranium filled out the space between the dermal skeleton and brain, like in galeaspids, osteostracans and placoderms and unlike in cyclostomes2. However, these cartilages are not fused into a single neurocranial unit, suggesting that this is a derived gnathostome trait. Eriptychius fills a major temporal and phylogenetic gap in our understanding of the evolution of the gnathostome head, revealing a neurocranium with an anatomy unlike that of any previously described vertebrate.
Assuntos
Fósseis , Filogenia , Crânio , Vertebrados , Animais , Feiticeiras (Peixe)/anatomia & histologia , Imageamento Tridimensional , Lampreias/anatomia & histologia , Boca , Bulbo Olfatório , Glândula Pineal , Crânio/anatomia & histologia , Tomógrafos Computadorizados , Vertebrados/anatomia & histologia , Vertebrados/classificação , Colorado , Cartilagem/anatomia & histologiaRESUMO
The eye is instrumental for controlling circadian rhythms in mice and human. Here, we address the conservation of this function in the zebrafish, a diurnal vertebrate. Using lakritz (lak) mutant larvae, which lack retinal ganglion cells (RGCs), we show that while a functional eye contributes to masking, it is largely dispensable for the establishment of circadian rhythms of locomotor activity. Furthermore, the eye is dispensable for the induction of a phase delay following a pulse of white light at CT 16 but contributes to the induction of a phase advance upon a pulse of white light at CT21. Melanopsin photopigments are important mediators of photoentrainment, as shown in nocturnal mammals. One of the zebrafish melanopsin genes, opn4xa, is expressed in RGCs but also in photosensitive projection neurons in the pineal gland. Pineal opn4xa+ projection neurons function in a LIGHT ON manner in contrast to other projection neurons which function in a LIGHT OFF mode. We generated an opn4xa mutant in which the pineal LIGHT ON response is impaired. This mutation has no effect on masking and circadian rhythms of locomotor activity, or for the induction of phase shifts, but slightly modifies period length when larvae are subjected to constant light. Finally, analysis of opn4xa;lak double mutant larvae did not reveal redundancy between the function of the eye and opn4xa in the pineal for the control of phase shifts after light pulses. Our results support the idea that the eye is not the sole mediator of light influences on circadian rhythms of locomotor activity and highlight differences in the circadian system and photoentrainment of behaviour between different animal models.
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Ritmo Circadiano , Opsinas , Glândula Pineal , Peixe-Zebra , Animais , Ritmo Circadiano/genética , Interneurônios , Larva/genética , Mamíferos , Opsinas/genética , Opsinas/metabolismo , Glândula Pineal/fisiologia , Células Ganglionares da Retina/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations in RB1 and DICER1, the role of epigenetic deregulation and cis-regulatory regions in PB pathogenesis and progression is largely unknown. Here, we generated genome-wide gene expression, chromatin accessibility, and H3K27ac profiles covering key time points of PB initiation and progression from pineal tissues of a mouse model of CCND1-driven PB. We identified PB-specific enhancers and super-enhancers, and found that in some cases, the accessible genome dynamics precede transcriptomic changes, a characteristic that is underexplored in tumor progression. During progression of PB, newly acquired open chromatin regions lacking H3K27ac signal become enriched for repressive state elements and harbor motifs of repressor transcription factors like HINFP, GLI2, and YY1. Copy number variant analysis identified deletion events specific to the tumorigenic stage, affecting, among others, the histone gene cluster and Gas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples, showing the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivo cis-regulatory, expression, and accessibility maps in PB.
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Neoplasias Encefálicas , Glândula Pineal , Pinealoma , Animais , Camundongos , Humanos , Criança , Cromatina , Pinealoma/genética , Histonas/metabolismo , Glândula Pineal/metabolismo , Neoplasias Encefálicas/genética , Elementos Facilitadores Genéticos , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.
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Melatonina , Glândula Pineal , Camundongos , Animais , Melatonina/metabolismo , Acetilserotonina O-Metiltransferasa/química , Acetilserotonina O-Metiltransferasa/metabolismo , alfa-Sinucleína/metabolismo , Glândula Pineal/metabolismoRESUMO
Retinoschisin (RS1) is a secretory protein specifically localized to the extracellular domains in both the lateral retina and the pineal gland (PG). However, the functions of RS1 in the pineal body are poorly understood. To address this knowledge gap, in this study, we undertook histochemical, ultrastructural, and Western blotting analyses of the PG in rats and RS1-knock-in transgenic. We found that RS1 plays a key role in pineal gland calcification (PGC) in mice through both extracellular and intracellular pathways. RS1 was clustered around the cell membrane or intracellularly in pinealocytes, actively participating in the exchange of calcium and thereby mediating PGC. Additionally, RS1 deposition is essential for maintaining PGC architecture in the intercellular space of the adult PG. In RS1-knock-in mice with a nonsense mutation (p.Y65X) in the Rs1-domain of RS1, the Rs1-domain is chaotically dispersed in pinealocytes and the intercellular region of the PG. This prevents RS1 from binding calcified spots and forming calcified nodules, ultimately leading to the accumulation of calcareous lamellae in microvesicles. Additionally, RS1 was observed to colocalize with connexin-36, thereby modulating intercellular communication in the PG of both rats and mice. Our study revealed for the first time that RS1 is essential for maintaining PGC architecture and that it colocalizes with connexin 36 to modulate intercellular communication in the PG. These findings provide novel insights into the function of the RS1 gene in the PG.
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Comunicação Celular , Glândula Pineal , Animais , Glândula Pineal/metabolismo , Ratos , Camundongos , Proteínas do Olho/metabolismo , Proteínas do Olho/genética , Calcinose/metabolismo , Calcinose/patologia , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Ratos Sprague-DawleyRESUMO
BACKGROUND: Aging affects anxiety levels in rats while the pineal gland, via its hormone melatonin, could modulate their inherited life "clock." The present study aimed to explore the impact of plasma melatonin deficiency on anxiety responses and the possible involvement of the hypothalamic-pituitary-adrenocortical (HPA) axis and heat shock proteins (Hsp) 70 and 90 in the frontal cortex (FC) and the hippocampus in young adult, middle-aged and elderly rats with pinealectomy. RESULTS: Melatonin deficiency induced at different life stages did not affect the lifespan of rats. Pinealectomy abolished the circadian rhythm of motor activity, measured for 48 h in the actimeter, in young adult but not in middle-aged rats. Pinealectomy reduced the motor activity of the young adult rats during the dark phase and impaired the diurnal activity variations of old rats. The same generations (3- and 18 month-old rats with pinealectomy) had lower anxiety levels than the matched sham groups, measured in three tests: elevated-plus maze, light-dark test, and novelty-suppressed feeding test. While the activity of the HPA axis remained intact in young adult and middle-aged rats with melatonin deficiency, a high baseline corticosterone level and blunted stress-induced mechanism of its release were detected in the oldest rats. Age-associated reduced Hsp 70 and 90 levels in the FC but not in the hippocampus were detected. Pinealectomy diminished the expression of Hsp 70 in the FC of middle-aged rats compared to the matched sham rats. CONCLUSIONS: Our results suggest that while melatonin hormonal dysfunction impaired the motor activity in the actimeter and emotional behavior in young adult and elderly rats, the underlying pathogenic mechanism in these generations might be different and needs further verification.
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Melatonina , Glândula Pineal , Humanos , Ratos , Animais , Pessoa de Meia-Idade , Lactente , Glândula Pineal/cirurgia , Glândula Pineal/fisiologia , Melatonina/farmacologia , Melatonina/fisiologia , Pinealectomia , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Ansiedade , Atividade MotoraRESUMO
INTRODUCTION: The superficial pineal gland of the Sprague Dawley rat is a neuroendocrine structure secreting the hormone melatonin. By use of block face scanning electron microscopy, our aim here was to identify the 3-dimensional ultrastructure of the gland. METHODS: A series of 2,731 block face images of the rat pineal tissue, 30 nm in thickness, was obtained in a Teneo volume scanning electron microscope and used for 3-dimensional reconstruction by use of the TrakEM2-plugin in the ImageJ software. Thin sections of the tissue were cut for transmission electron microscopy. RESULTS: Our analyses revealed cellular bulbous processes, containing 50-100 nm clear vesicles, that emerged from a neck-like area at the cell body of the pinealocyte. These bulbous processes extend into small canaliculi located in the center of parenchymal folliculi of the gland as well as into the perivascular spaces. Junctional complexes, comprising both gap and tight junctions, connected the lateral cellular membranes of the pinealocytes, where the bulbous processes emerged from the cell bodies. The canaliculi were, via the extracellular space, connected to the perivascular spaces. DISCUSSION: The junctional complexes reported here would prevent a substance, released from the vesicles in the bulbous processes, from targeting the cell body from which they emerge. In line with previous combined morphological and biochemical demonstrations of glutamate located in clear vesicles of bulbous processes in the rat pineal gland, our data ultrastructurally support the concept that bulbous processes could participate in a paracrine glutamatergic inhibition of the melatonin secretion in the pineal gland. CONCLUSION: Bulbous secretory projections separated from the cell body by a junctional complex represents a new feature of neuroendocrine cells.
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Melatonina , Glândula Pineal , Ratos , Animais , Corpo Celular , Ratos Sprague-Dawley , Melatonina/metabolismo , Glândula Pineal/metabolismoRESUMO
PURPOSE: To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT). METHODS: Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases. RESULTS: Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3-6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively. CONCLUSION: PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies.
Assuntos
Neoplasias Encefálicas , Glândula Pineal , Pinealoma , Neoplasias Supratentoriais , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Adulto Jovem , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/cirurgia , Recidiva Local de Neoplasia/patologia , Glândula Pineal/cirurgia , Glândula Pineal/patologia , Pinealoma/diagnóstico , Pinealoma/cirurgia , Recidiva , Neoplasias Supratentoriais/patologia , Resultado do TratamentoRESUMO
We assessed the circadian clock control of singing and reproductive performance in zebra finches. Experiment 1 examined changes in body mass, testis size, and plasma corticosterone and testosterone levels in male birds exposed to constant light (LL, 100 lx) and constant darkness (DD, 0.5 lx), with controls on 12L:12D (L = 100 lx, D = 0.5 lx). There was a significant increase in the body mass and testis size under LL and a decrease in testis size under the DD. Using a similar design, experiment 2 assessed the persistence of the circadian rhythm in singing along with activity-rest pattern in cohort I birds that were entrained to 12L:12D and subsequently released in DD or LL, and in cohort II birds that were entrained to 12L:12D and following pinealectomy were released in DD. Both activity and singing patterns were synchronized with the light phase under 12L:12D, free-ran with a circadian period under DD, and were arrhythmic under the LL. There was an overall decreased and increased effect on singing under DD and LL, respectively, albeit with differences in various song parameters. The pinealectomy disrupted both activity and singing rhythms but did not affect singing or the overall song features. Pinealectomized bird pairs also exhibited a significant reduction in their nest-building and breeding efforts, resulting in a compromised reproductive performance. These results suggest a circadian clock control of singing and more importantly demonstrate a role of the pineal clock in breeding behaviors, leading to a compromised reproductive performance in diurnal zebra finches.
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Tentilhões , Glândula Pineal , Humanos , Masculino , Animais , Pinealectomia , Luz , Ritmo Circadiano , Glândula Pineal/cirurgia , FotoperíodoRESUMO
The pineal gland has evolved from a photoreceptive organ in fish to a neuroendocrine organ in mammals. This study integrated multiple daytime single-cell RNA-seq datasets from the pineal glands of zebrafish, rats, and monkeys, providing a detailed examination of the evolutionary transition at single-cell resolution. We identified key factors responsible for the anatomical and functional transformation of the pineal gland. We retrieved and integrated daytime single-cell transcriptomic datasets from the pineal glands of zebrafish, rats, and monkeys, resulting in a total of 22 431 cells after rigorous quality filtering. Comparative analysis was then conducted to elucidate the evolution of pineal cells, their photosensitivity, their role in melatonin production, and the signaling processes within the glands of these species. Our analysis identified distinct cellular compositions of the pineal gland in zebrafish, rats, and monkeys. Zebrafish photoreceptors exhibited comprehensive phototransduction gene expression, while specific genes, including transducin (Gngt1, Gnb3, and Gngt2) and phosducin (Pdc), were consistently present in mammalian pinealocytes. We found transcriptional similarities between the pineal gland and retina, underscoring shared evolutionary and functional pathways. Zebrafish displayed unique light-responsive circadian gene activity compared to rats and monkeys. Key ligand-receptor interactions were identified, especially involving MDK and PTN, influencing melatonin synthesis across species. Furthermore, we observed species-specific GPCR (G protein-coupled receptors) expressions related to melatonin synthesis and their alignment with retinal expressions. Our findings also highlighted specific transcription factors (TFs) and regulatory networks associated with pineal gland evolution and function. Our study provides a detailed analysis of the pineal gland's evolution from fish to mammals. We identified key transcriptional changes and controls that highlight the gland's functional diversity. Notably, we found significant ligand-receptor interactions influencing melatonin synthesis and demonstrated parallels between pineal and retinal expressions. These insights enhance our understanding of the pineal gland's role in phototransduction, melatonin production, and circadian rhythms in vertebrates.
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Melatonina , Glândula Pineal , Animais , Ratos , Glândula Pineal/metabolismo , Melatonina/metabolismo , Peixe-Zebra/genética , Ligantes , Ritmo Circadiano/genética , Mamíferos/metabolismoRESUMO
Immune-pineal axis activation is part of the assembly of immune responses. Proinflammatory cytokines inhibit the pineal synthesis of melatonin while inducing it in macrophages by mechanisms dependent on nuclear factor-κB (NF-κB) activation. Cytokines activating the Janus kinase/signal transducer and activator of transcription (STAT) pathways, such as interferon-gamma (IFN-γ) and interleukin-10 (IL-10), modulate melatonin synthesis in the pineal, bone marrow (BM), and spleen. The stimulatory effect of IFN-γ upon the pineal gland depends on STAT1/NF-κB interaction, but the mechanisms controlling IL-10 effects on melatonin synthesis remain unclear. Here, we evaluated the role of STAT3 and NF-κB activation by IL-10 upon the melatonin synthesis of rats' pineal gland, BM, spleen, and peritoneal cells. The results show that IL-10-induced interaction of (p)STAT3 with specific NF-κB dimmers leads to different cell effects. IL-10 increases the pineal's acetylserotonin O-methyltransferase (ASMT), N-acetylserotonin, and melatonin content via nuclear translocation of NF-κB/STAT3. In BM, the nuclear translocation of STAT3/p65-NF-κB complexes increases ASMT expression and melatonin content. Increased pSTAT3/p65-NF-κB nuclear translocation in the spleen enhances phosphorylated serotonin N-acetyltransferase ((p)SNAT) expression and melatonin content. Conversely, in peritoneal cells, IL-10 leads to NF-κB p50/p50 inhibitory dimmer nuclear translocation, decreasing (p)SNAT expression and melatonin content. In conclusion, IL-10's effects on melatonin production depend on the NF-κB subunits interacting with (p)STAT3. Thus, variations of IL-10 levels and downstream pathways during immune responses might be critical regulatory factors adjusting pineal and extra-pineal synthesis of melatonin.
Assuntos
Melatonina , Glândula Pineal , Ratos , Animais , NF-kappa B/metabolismo , Glândula Pineal/metabolismo , Melatonina/farmacologia , Interleucina-10/metabolismo , Transdução de SinaisRESUMO
In mammals, seasonal opportunities and challenges are anticipated through programmed changes in physiology and behavior. Appropriate anticipatory timing depends on synchronization to the external solar year, achieved through the use of day length (photoperiod) as a synchronizing signal. In mammals, nocturnal production of melatonin by the pineal gland is the key hormonal mediator of photoperiodic change, exerting its effects via the hypothalamopituitary axis. In this review/perspective, we consider the key developments during the history of research into the seasonal synchronizer effect of melatonin, highlighting the role that the pars tuberalis-tanycyte module plays in this process. We go on to consider downstream pathways, which include discrete hypothalamic neuronal populations. Neurons that express the neuropeptides kisspeptin and (Arg)(Phe)-related peptide-3 (RFRP-3) govern seasonal reproductive function while neurons that express somatostatin may be involved in seasonal metabolic adaptations. Finally, we identify several outstanding questions, which need to be addressed to provide a much thorough understanding of the deep impact of melatonin upon seasonal synchronization.
Assuntos
Mamíferos , Melatonina , Estações do Ano , Melatonina/metabolismo , Animais , Mamíferos/metabolismo , Fotoperíodo , Humanos , Glândula Pineal/metabolismoRESUMO
Melatonin is a small natural compound, so called a neuro-hormone that is synthesized mainly in pineal gland in animals. Its main role is to master the clock of the body, under the surveillance of light. In other words, it transfers the information concerning night and day to the peripheral organs which, without it, could not "know" which part of the circadian rhythm the body is in. Besides its main circadian and circannual rhythms mastering, melatonin is reported to be a radical scavenger and/or an antioxidant. Because radical scavengers are chemical species able to neutralize highly reactive and toxic species such as reactive oxygen species, one would like to transfer this property to living system, despite impossibilities already largely reported in the literature. In the present commentary, we refresh the memory of the readers with this notion of radical scavenger, and review the possible evidence that melatonin could be an in vivo radical scavenger, while we only marginally discuss here the fact that melatonin is a molecular antioxidant, a feature that merits a review on its own. We conclude four things: (i) the evidence that melatonin is a scavenger in acellular systems is overwhelming and could not be doubted; (ii) the transposition of this property in living (animal) systems is (a) theoretically impossible and (b) not proven in any system reported in the literature where most of the time, the delay of the action of melatonin is over several hours, thus signing a probable induction of cellular enzymatic antioxidant defenses; (iii) this last fact needs a confirmation through the discovery of a nuclear factor-a key relay in induction processes-that binds melatonin and is activated by it and (iv) we also gather the very important description of the radical scavenging capacity of melatonin in acellular systems that is now proven and shared by many other double bond-bearing molecules. We finally discussed briefly on the reason-scientific or else-that led this description, and the consequences of this claim, in research, in physiology, in pathology, but most disturbingly in therapeutics where a vast amount of money, hope, and patient bien-être are at stake.
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Melatonina , Glândula Pineal , Animais , Humanos , Melatonina/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glândula Pineal/metabolismo , Ritmo Circadiano/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Temporal signals such as light and temperature cycles profoundly modulate animal physiology and behaviour. Via endogenous timing mechanisms which are regulated by these signals, organisms can anticipate cyclic environmental changes and thereby enhance their fitness. The pineal gland in fish, through the secretion of melatonin, appears to play a critical role in the circadian system, most likely acting as an element of the circadian clock system. An important output of this circadian clock is the locomotor activity circadian rhythm which is adapted to the photoperiod and thus determines whether animals are diurnal or nocturnal. By using a genetically modified zebrafish strain known as Tg (Xla.Eef1a1:Cau.asip1)iim04, which expresses a higher level of the agouti signalling protein 1 (Asip1), an endogenous antagonist of the melanocortin system, we observed a complete disruption of locomotor activity patterns, which correlates with the ablation of the melatonin daily rhythm. Consistent with this, in vitro experiments also demonstrated that Asip1 inhibits melatonin secretion from the zebrafish pineal gland, most likely through the melanocortin receptors expressed in this gland. Asip1 overexpression also disrupted the expression of core clock genes, including per1a and clock1a, thus blunting circadian oscillation. Collectively, these results implicate the melanocortin system as playing an important role in modulating pineal physiology and, therefore, circadian organisation in zebrafish.
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Melanocortinas , Melatonina , Glândula Pineal , Animais , Proteína Agouti Sinalizadora/genética , Proteína Agouti Sinalizadora/metabolismo , Ritmo Circadiano/fisiologia , Locomoção/fisiologia , Melatonina/metabolismo , Glândula Pineal/metabolismo , Peixe-Zebra/genética , Melanocortinas/metabolismoRESUMO
Homeobox genes encode transcription factors that are widely known to control developmental processes. This is also the case in the pineal gland, a neuroendocrine brain structure devoted to nighttime synthesis of the hormone melatonin. Thus, in accordance with high prenatal gene expression, knockout studies have identified a specific set of homeobox genes that are essential for development of the pineal gland. However, as a special feature of the pineal gland, homeobox gene expression persists into adulthood, and gene product abundance exhibits 24 h circadian rhythms. Recent lines of evidence show that some homeobox genes even control expression of enzymes catalyzing melatonin synthesis. We here review current knowledge of homeobox genes in the rodent pineal gland and suggest a model for dual functions of homeobox gene-encoded transcription factors in developmental and circadian mature neuroendocrine function.
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Melatonina , Glândula Pineal , Animais , Glândula Pineal/metabolismo , Genes Homeobox , Melatonina/metabolismo , Roedores/genética , Roedores/metabolismo , Fatores de Transcrição/metabolismo , Ritmo CircadianoRESUMO
This contribution reviews the role of inbred and transgenic mouse strains for deciphering the mammalian melatoninergic and circadian system. It focusses on the pineal organ as melatonin factory and two major targets of the melatoninergic system, the suprachiasmatic nuclei (SCN) and the hypophysial pars tuberalis (PT). Mammalian pinealocytes sharing molecular characteristics with true pineal and retinal photoreceptors synthesize and secrete melatonin into the blood and cerebrospinal fluid night by night. Notably, neuron-like connections exist between the deep pinealocytes and the habenular/pretectal region suggesting direct pineal-brain communication. Control of melatonin biosynthesis in rodents involves transcriptional regulation including phosphorylation of CREB and upregulation of mPer1. In the SCN, melatonin acts upon MT1 and MT2 receptors. Melatonin is not necessary to maintain the rhythm of the SCN molecular clockwork, but it has distinct effects on the synchronization of the circadian rhythm by light, facilitates re-entrainment of the circadian system to phase advances in the level of the SCN molecular clockwork by acting upon MT2 receptors and plays a stabilizing role in the circadian system as evidenced from locomotor activity recordings. While the effects in the SCN are subtle, melatonin is essential for PT functions. Via the MT1 receptor it drives the PT-intrinsic molecular clockwork and the retrograde and anterograde output pathways controlling seasonal rhythmicity. Although inbred and transgenic mice do not show seasonal reproduction, the pathways from the PT are fully intact if the animals are melatonin proficient. Thus, only melatonin-proficient strains are suited to investigate the circadian and melatoninergic systems.
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Ritmo Circadiano , Melatonina , Animais , Melatonina/metabolismo , Ritmo Circadiano/fisiologia , Camundongos , Modelos Animais , Núcleo Supraquiasmático/metabolismo , Camundongos Transgênicos , Glândula Pineal/metabolismoRESUMO
Melatonin is a neurohormone synthesized from dietary tryptophan in various organs, including the pineal gland and the retina. In the pineal gland, melatonin is produced at night under the control of the master clock located in the suprachiasmatic nuclei of the hypothalamus. Under physiological conditions, the pineal gland seems to constitute the unique source of circulating melatonin. Melatonin is involved in cellular metabolism in different ways. First, the circadian rhythm of melatonin helps the maintenance of proper internal timing, the disruption of which has deleterious effects on metabolic health. Second, melatonin modulates lipid metabolism, notably through diminished lipogenesis, and it has an antidiabetic effect, at least in several animal models. Third, pharmacological doses of melatonin have antioxidative, free radical-scavenging, and anti-inflammatory properties in various in vitro cellular models. As a result, melatonin can be considered both a circadian time-giver and a homeostatic monitor of cellular metabolism, via multiple mechanisms of action that are not all fully characterized. Aging, circadian disruption, and artificial light at night are conditions combining increased metabolic risks with diminished circulating levels of melatonin. Accordingly, melatonin supplementation could be of potential therapeutic value in the treatment or prevention of metabolic disorders. More clinical trials in controlled conditions are needed, notably taking greater account of circadian rhythmicity.
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Ritmo Circadiano , Homeostase , Melatonina , Melatonina/metabolismo , Animais , Humanos , Ritmo Circadiano/fisiologia , Homeostase/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Glândula Pineal/metabolismoRESUMO
Pineal lesions represent less than 1% of all brain tumors (Villani et al., Clin Neurol Neurosurg 109:1-6, 2007). The abysmal location and critical neurovascular structures remain a surgical challenge, despite the advent of microneurosurgery. The classical wide surgical suboccipital craniotomy with the supracerebellar infratentorial approach, described by Sir Victor Horsley (Victor, Proc R Soc Med 3:77-78, 1910), is infamous for its considerable surgical morbidity and mortality. This was later upgraded microneurosurgically by Stein to improve surgical outcomes (Stein, J Neurosurg 35:197-202, 1971).Ruge et al. reported the first purely endoscopic fenestration of quadrigeminal arachnoid cysts via this corridor (Ruge et al., Neurosurgery 38:830-7, 1996). A cadaver-based anatomical study by Cardia et al. demonstrated the viability for endoscope-assisted techniques (Cardia et al., J Neurosurg 2006;104(6 Suppl):409-14). However, the first purely endoscopic supracerebellar infratentorial (eSCIT) approach to a pineal cyst was performed in 2008 by Gore et al. (Gore PA et al., Neurosurgery 62:108-9, 2008).Unlike transventricular endoscopy, eSCIT approach poses no mechanical risk to the fornices and can be utilized irrespective of ventricular size. More vascular control and resultant reduction in uncontrolled hemorrhage improve the feasibility of attaining complete resection, especially around corners (Zaidi et al,, World Neurosurg 84, 2015). Gravity-dependent positioning and cerebrospinal fluid (CSF) diversion aid cerebellar relaxation, creating the ideal anatomical pathway. Also, angle of the straight sinus, tentorium, and tectal adherence can often influence the choice of approach; thus direct endoscopic visualization not only counteracts access to the engorged Galenic complex but also encourages sharp dissection of the arachnoid (Cardia et al., J Neurosurg 104:409-14, 2006). These tactics help provide excellent illumination with magnification, making it less fatiguing for the surgeon (Broggi et al., Neurosurgery 67:159-65, 2010).The purely endoscopic approach thwarts the dreaded risk of air embolisms, via simple copious irrigation from a small burr hole (Shahinian and Ra, J Neurol Surg B Skull Base 74:114-7, 2013). The tiny opening and closure are rapid to create, and the smaller wound decreases postoperative pain and morbidity. Recent literature supports its numerous advantages and favorable outcomes, making it a tough contender to traditional open methods.
Assuntos
Glândula Pineal , Criança , Humanos , Neoplasias Encefálicas/cirurgia , Cerebelo/cirurgia , Endoscopia/métodos , Neuroendoscopia/métodos , Procedimentos Neurocirúrgicos/métodos , Glândula Pineal/cirurgia , Pinealoma/cirurgiaRESUMO
Germline mutations of NSD1 are associated with Sotos syndrome, characterized by distinctive facial features, overgrowth, and developmental delay. Approximately 3% of individuals with Sotos syndrome develop tumors. In this study, we describe an infant in pineoblastoma with facial anomalies, learning disability and mild autism at 1 years diagnosed as Sotos syndrome owing to carrying a novel mutation de novo germline NSD1 likely pathogenic variant. This patient expands both the mutation and phenotype spectrum of the Sotos Syndrome and provides new clinical insights into the potential mechanism of underlying pinealoblastoma pathology.
Assuntos
Neoplasias Encefálicas , Glândula Pineal , Pinealoma , Síndrome de Sotos , Lactente , Humanos , Síndrome de Sotos/complicações , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/genética , Histona-Lisina N-Metiltransferase/genética , Histona Metiltransferases/genética , Mutação em Linhagem Germinativa , Pinealoma/complicações , Pinealoma/genética , Mutação , Glândula Pineal/patologiaRESUMO
PURPOSE: Access to the pineal region has always represented a fascinating challenge to the neurosurgeons. Almost equally thrilling is the historical evolution from the hard beginnings with extremely high mortality rates to the current surgical outcomes, with excellent resection rates without long-term morbidity for most of the patients. The purpose of this paper is to provide an overview of the historical evolution of the occipital interhemispheric transtentorial (OITT) approach and its role in the development of access to the pineal region. METHODS: Review of the literature highlights the occipital transtentorial approach from the historical context prior its description and the beginning to the current modifications and new recent insights. RESULTS: The occipital transtentorial approach described initially by Poppen in 1966 has played a key role in the progress and success accessing the pineal area. CONCLUSION: This historical review aims to highlight the extraordinary effort of those neurosurgeons who guided and led the development of one of the most important approaches to the pineal region.