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David C Klein - One of the best experts on this subject based on the ideXlab platform.
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circadian regulation and molecular role of the bsx homeobox gene in the adult Pineal Gland
Journal of Pineal Research, 2020Co-Authors: Mikkel Bloss Carstensen, Morten Møller, Kristian Rohde, David C Klein, Steven L Coon, Henrik Hertz, Tenna Bering, Martin F. RathAbstract:The Pineal Gland is a neuroendocrine organ responsible for production of the nocturnal hormone melatonin. A specific set of homeobox gene-encoded transcription factors govern Pineal development, and some are expressed in adulthood. The brain-specific homeobox gene (Bsx) falls into both categories. We here examined regulation and function of Bsx in the mature Pineal Gland of the rat. We report that Bsx is expressed from prenatal stages into adulthood, where Bsx transcripts are localized in the melatonin-synthesizing Pinealocytes, as revealed by RNAscope in situ hybridization. Bsx transcripts were also detected in the adult human Pineal Gland. In the rat Pineal Gland, Bsx was found to exhibit a 10-fold circadian rhythm with a peak at night. By combining in vivo adrenergic stimulation and surgical denervation of the Gland in the rat with in vitro stimulation and transcriptional inhibition in cultured Pinealocytes, we show that rhythmic expression of Bsx is controlled at the transcriptional level by the sympathetic neural input to the Gland acting via adrenergic stimulation with cyclic AMP as a second messenger. siRNA-mediated knockdown (>80% reduction) in Pinealocyte cultures revealed Bsx to be a negative regulator of other Pineal homeobox genes, including paired box 4 (Pax4), but no effect on genes encoding melatonin-synthesizing enzymes was detected. RNA sequencing analysis performed on siRNA-treated Pinealocytes further revealed that downstream target genes of Bsx are mainly involved in developmental processes. Thus, rhythmic Bsx expression seems to govern other developmental regulators in the mature Pineal Gland.
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Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland
Endocrinology, 2016Co-Authors: Martin F. Rath, Fernanda Gaspar Do Amaral, Morten Møller, Joan L Weller, David C KleinAbstract:The rat Pineal Gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat Pineal Gland, marked cell-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in Pinealocytes in the parenchyma of the superficial Pineal Gland, and immunopositive Pinealocytes were also detected in the Pineal stalk and in the deep Pineal Gland. ASMT was found to inconsistently colocalize with S-antigen, a widely used Pinealocyte marker; this colocalization was seen in cells throughout the Pineal complex and also in displaced Pinealocyte-like cells of the medial habenular nucleus. Inconsistent colocalization between ASMT and TPH protein was also detected in the Pineal Gland. ASMT protein was not detected in extraepithalamic parts of the central nervous system or in peripheral tissues. The findings in this report are of special interest because they provide reason to suspect that melatonin synthesis varies significantly among individual Pinealocytes.
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the lhx9 homeobox gene controls Pineal Gland development and prevents postnatal hydrocephalus
Brain Structure & Function, 2015Co-Authors: Fumiyoshi Yamazaki, Morten Møller, David C Klein, Samuel Clokie, Artem Zykovich, Steven L Coon, Martin F. RathAbstract: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.
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Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance
Neurochemical Research, 2013Co-Authors: Martin F. Rath, Kristian Rohde, David C Klein, Morten MøllerAbstract:The Pineal Gland is a neuroendocrine Gland responsible for nocturnal synthesis of melatonin. During early development of the rodent Pineal Gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal Pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the Pineal Gland appears to be unusual because strong homeobox gene expression persists in the Pineal Gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of Pineal development and recent progress in understanding the involvement of homebox genes in rodent Pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian Pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the Pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the Pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.
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rgs2 is a feedback inhibitor of melatonin production in the Pineal Gland
FEBS Letters, 2013Co-Authors: Masahiro Matsuo, Steven L Coon, David C KleinAbstract:The 24-h rhythmic production of melatonin by the Pineal Gland is essential for coordinating circadian physiology. Melatonin production increases at night in response to the release of norepinephrine from sympathetic nerve processes which innervate the Pineal Gland. This signal is transduced through G-protein-coupled adrenergic receptors. Here, we found that the abundance of regulator of G-protein signaling 2 (RGS2) increases at night, that expression is increased by norepinephrine and that this protein has a negative feedback effect on melatonin production. These data are consistent with the conclusion that RGS2 functions on a daily basis to negatively modulate melatonin production.
Morten Møller - One of the best experts on this subject based on the ideXlab platform.
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circadian regulation and molecular role of the bsx homeobox gene in the adult Pineal Gland
Journal of Pineal Research, 2020Co-Authors: Mikkel Bloss Carstensen, Morten Møller, Kristian Rohde, David C Klein, Steven L Coon, Henrik Hertz, Tenna Bering, Martin F. RathAbstract:The Pineal Gland is a neuroendocrine organ responsible for production of the nocturnal hormone melatonin. A specific set of homeobox gene-encoded transcription factors govern Pineal development, and some are expressed in adulthood. The brain-specific homeobox gene (Bsx) falls into both categories. We here examined regulation and function of Bsx in the mature Pineal Gland of the rat. We report that Bsx is expressed from prenatal stages into adulthood, where Bsx transcripts are localized in the melatonin-synthesizing Pinealocytes, as revealed by RNAscope in situ hybridization. Bsx transcripts were also detected in the adult human Pineal Gland. In the rat Pineal Gland, Bsx was found to exhibit a 10-fold circadian rhythm with a peak at night. By combining in vivo adrenergic stimulation and surgical denervation of the Gland in the rat with in vitro stimulation and transcriptional inhibition in cultured Pinealocytes, we show that rhythmic expression of Bsx is controlled at the transcriptional level by the sympathetic neural input to the Gland acting via adrenergic stimulation with cyclic AMP as a second messenger. siRNA-mediated knockdown (>80% reduction) in Pinealocyte cultures revealed Bsx to be a negative regulator of other Pineal homeobox genes, including paired box 4 (Pax4), but no effect on genes encoding melatonin-synthesizing enzymes was detected. RNA sequencing analysis performed on siRNA-treated Pinealocytes further revealed that downstream target genes of Bsx are mainly involved in developmental processes. Thus, rhythmic Bsx expression seems to govern other developmental regulators in the mature Pineal Gland.
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Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland
Endocrinology, 2016Co-Authors: Martin F. Rath, Fernanda Gaspar Do Amaral, Morten Møller, Joan L Weller, David C KleinAbstract:The rat Pineal Gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat Pineal Gland, marked cell-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in Pinealocytes in the parenchyma of the superficial Pineal Gland, and immunopositive Pinealocytes were also detected in the Pineal stalk and in the deep Pineal Gland. ASMT was found to inconsistently colocalize with S-antigen, a widely used Pinealocyte marker; this colocalization was seen in cells throughout the Pineal complex and also in displaced Pinealocyte-like cells of the medial habenular nucleus. Inconsistent colocalization between ASMT and TPH protein was also detected in the Pineal Gland. ASMT protein was not detected in extraepithalamic parts of the central nervous system or in peripheral tissues. The findings in this report are of special interest because they provide reason to suspect that melatonin synthesis varies significantly among individual Pinealocytes.
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the lhx9 homeobox gene controls Pineal Gland development and prevents postnatal hydrocephalus
Brain Structure & Function, 2015Co-Authors: Fumiyoshi Yamazaki, Morten Møller, David C Klein, Samuel Clokie, Artem Zykovich, Steven L Coon, Martin F. RathAbstract: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.
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Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance
Neurochemical Research, 2013Co-Authors: Martin F. Rath, Kristian Rohde, David C Klein, Morten MøllerAbstract:The Pineal Gland is a neuroendocrine Gland responsible for nocturnal synthesis of melatonin. During early development of the rodent Pineal Gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal Pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the Pineal Gland appears to be unusual because strong homeobox gene expression persists in the Pineal Gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of Pineal development and recent progress in understanding the involvement of homebox genes in rodent Pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian Pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the Pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the Pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.
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rax developmental and daily expression patterns in the rat Pineal Gland and retina
Journal of Neurochemistry, 2011Co-Authors: Kristian Rohde, Morten Møller, David C Klein, Martin F. RathAbstract:J. Neurochem. (2011) 118, 999–1007. Abstract Retina and anterior neural fold homeobox (Rax) gene encodes a transcription factor essential for vertebrate eye development. Recent microarray studies indicate that Rax is expressed in the adult rat Pineal Gland and retina. The present study reveals that Rax expression levels in the rat change significantly during retinal development with a peak occurring at embryonic day 18, whereas Rax expression in the Pineal is relatively delayed and not detectable until embryonic day 20. In both tissues, Rax is expressed throughout postnatal development into adulthood. In the mature rat Pineal Gland, the abundance of Rax transcripts increases 2-fold during the light period with a peak occurring at dusk. These findings are consistent with the evidence that Rax is of functional importance in eye development and suggest a role of Rax in the developing Pineal Gland. In addition, it would appear possible that Rax contributes to phenotype maintenance in the mature retina and Pineal Gland and may facilitate 24-h changes in the Pineal transcriptome.
Martin F. Rath - One of the best experts on this subject based on the ideXlab platform.
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circadian regulation and molecular role of the bsx homeobox gene in the adult Pineal Gland
Journal of Pineal Research, 2020Co-Authors: Mikkel Bloss Carstensen, Morten Møller, Kristian Rohde, David C Klein, Steven L Coon, Henrik Hertz, Tenna Bering, Martin F. RathAbstract:The Pineal Gland is a neuroendocrine organ responsible for production of the nocturnal hormone melatonin. A specific set of homeobox gene-encoded transcription factors govern Pineal development, and some are expressed in adulthood. The brain-specific homeobox gene (Bsx) falls into both categories. We here examined regulation and function of Bsx in the mature Pineal Gland of the rat. We report that Bsx is expressed from prenatal stages into adulthood, where Bsx transcripts are localized in the melatonin-synthesizing Pinealocytes, as revealed by RNAscope in situ hybridization. Bsx transcripts were also detected in the adult human Pineal Gland. In the rat Pineal Gland, Bsx was found to exhibit a 10-fold circadian rhythm with a peak at night. By combining in vivo adrenergic stimulation and surgical denervation of the Gland in the rat with in vitro stimulation and transcriptional inhibition in cultured Pinealocytes, we show that rhythmic expression of Bsx is controlled at the transcriptional level by the sympathetic neural input to the Gland acting via adrenergic stimulation with cyclic AMP as a second messenger. siRNA-mediated knockdown (>80% reduction) in Pinealocyte cultures revealed Bsx to be a negative regulator of other Pineal homeobox genes, including paired box 4 (Pax4), but no effect on genes encoding melatonin-synthesizing enzymes was detected. RNA sequencing analysis performed on siRNA-treated Pinealocytes further revealed that downstream target genes of Bsx are mainly involved in developmental processes. Thus, rhythmic Bsx expression seems to govern other developmental regulators in the mature Pineal Gland.
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Melatonin Synthesis: Acetylserotonin O-Methyltransferase (ASMT) Is Strongly Expressed in a Subpopulation of Pinealocytes in the Male Rat Pineal Gland
Endocrinology, 2016Co-Authors: Martin F. Rath, Fernanda Gaspar Do Amaral, Morten Møller, Joan L Weller, David C KleinAbstract:The rat Pineal Gland has been extensively used in studies of melatonin synthesis. However, the cellular localization of melatonin synthesis in this species has not been investigated. Here we focus on the localization of melatonin synthesis using immunohistochemical methods to detect the last enzyme in melatonin synthesis, acetylserotonin O-methyltransferase (ASMT), and in situ hybridization techniques to study transcripts encoding ASMT and two other enzymes in melatonin synthesis, tryptophan hydroxylase (TPH)-1 and aralkylamine N-acetyltransferase. In sections of the rat Pineal Gland, marked cell-to-cell differences were found in ASMT immunostaining intensity and in the abundance of Tph1, Aanat, and Asmt transcripts. ASMT immunoreactivity was localized to the cytoplasm in Pinealocytes in the parenchyma of the superficial Pineal Gland, and immunopositive Pinealocytes were also detected in the Pineal stalk and in the deep Pineal Gland. ASMT was found to inconsistently colocalize with S-antigen, a widely used Pinealocyte marker; this colocalization was seen in cells throughout the Pineal complex and also in displaced Pinealocyte-like cells of the medial habenular nucleus. Inconsistent colocalization between ASMT and TPH protein was also detected in the Pineal Gland. ASMT protein was not detected in extraepithalamic parts of the central nervous system or in peripheral tissues. The findings in this report are of special interest because they provide reason to suspect that melatonin synthesis varies significantly among individual Pinealocytes.
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the lhx9 homeobox gene controls Pineal Gland development and prevents postnatal hydrocephalus
Brain Structure & Function, 2015Co-Authors: Fumiyoshi Yamazaki, Morten Møller, David C Klein, Samuel Clokie, Artem Zykovich, Steven L Coon, Martin F. RathAbstract: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.
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Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance
Neurochemical Research, 2013Co-Authors: Martin F. Rath, Kristian Rohde, David C Klein, Morten MøllerAbstract:The Pineal Gland is a neuroendocrine Gland responsible for nocturnal synthesis of melatonin. During early development of the rodent Pineal Gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal Pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the Pineal Gland appears to be unusual because strong homeobox gene expression persists in the Pineal Gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of Pineal development and recent progress in understanding the involvement of homebox genes in rodent Pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian Pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the Pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the Pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.
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rax developmental and daily expression patterns in the rat Pineal Gland and retina
Journal of Neurochemistry, 2011Co-Authors: Kristian Rohde, Morten Møller, David C Klein, Martin F. RathAbstract:J. Neurochem. (2011) 118, 999–1007. Abstract Retina and anterior neural fold homeobox (Rax) gene encodes a transcription factor essential for vertebrate eye development. Recent microarray studies indicate that Rax is expressed in the adult rat Pineal Gland and retina. The present study reveals that Rax expression levels in the rat change significantly during retinal development with a peak occurring at embryonic day 18, whereas Rax expression in the Pineal is relatively delayed and not detectable until embryonic day 20. In both tissues, Rax is expressed throughout postnatal development into adulthood. In the mature rat Pineal Gland, the abundance of Rax transcripts increases 2-fold during the light period with a peak occurring at dusk. These findings are consistent with the evidence that Rax is of functional importance in eye development and suggest a role of Rax in the developing Pineal Gland. In addition, it would appear possible that Rax contributes to phenotype maintenance in the mature retina and Pineal Gland and may facilitate 24-h changes in the Pineal transcriptome.
Steven L Coon - One of the best experts on this subject based on the ideXlab platform.
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circadian regulation and molecular role of the bsx homeobox gene in the adult Pineal Gland
Journal of Pineal Research, 2020Co-Authors: Mikkel Bloss Carstensen, Morten Møller, Kristian Rohde, David C Klein, Steven L Coon, Henrik Hertz, Tenna Bering, Martin F. RathAbstract:The Pineal Gland is a neuroendocrine organ responsible for production of the nocturnal hormone melatonin. A specific set of homeobox gene-encoded transcription factors govern Pineal development, and some are expressed in adulthood. The brain-specific homeobox gene (Bsx) falls into both categories. We here examined regulation and function of Bsx in the mature Pineal Gland of the rat. We report that Bsx is expressed from prenatal stages into adulthood, where Bsx transcripts are localized in the melatonin-synthesizing Pinealocytes, as revealed by RNAscope in situ hybridization. Bsx transcripts were also detected in the adult human Pineal Gland. In the rat Pineal Gland, Bsx was found to exhibit a 10-fold circadian rhythm with a peak at night. By combining in vivo adrenergic stimulation and surgical denervation of the Gland in the rat with in vitro stimulation and transcriptional inhibition in cultured Pinealocytes, we show that rhythmic expression of Bsx is controlled at the transcriptional level by the sympathetic neural input to the Gland acting via adrenergic stimulation with cyclic AMP as a second messenger. siRNA-mediated knockdown (>80% reduction) in Pinealocyte cultures revealed Bsx to be a negative regulator of other Pineal homeobox genes, including paired box 4 (Pax4), but no effect on genes encoding melatonin-synthesizing enzymes was detected. RNA sequencing analysis performed on siRNA-treated Pinealocytes further revealed that downstream target genes of Bsx are mainly involved in developmental processes. Thus, rhythmic Bsx expression seems to govern other developmental regulators in the mature Pineal Gland.
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the lhx9 homeobox gene controls Pineal Gland development and prevents postnatal hydrocephalus
Brain Structure & Function, 2015Co-Authors: Fumiyoshi Yamazaki, Morten Møller, David C Klein, Samuel Clokie, Artem Zykovich, Steven L Coon, Martin F. RathAbstract: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.
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rgs2 is a feedback inhibitor of melatonin production in the Pineal Gland
FEBS Letters, 2013Co-Authors: Masahiro Matsuo, Steven L Coon, David C KleinAbstract:The 24-h rhythmic production of melatonin by the Pineal Gland is essential for coordinating circadian physiology. Melatonin production increases at night in response to the release of norepinephrine from sympathetic nerve processes which innervate the Pineal Gland. This signal is transduced through G-protein-coupled adrenergic receptors. Here, we found that the abundance of regulator of G-protein signaling 2 (RGS2) increases at night, that expression is increased by norepinephrine and that this protein has a negative feedback effect on melatonin production. These data are consistent with the conclusion that RGS2 functions on a daily basis to negatively modulate melatonin production.
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a new cis acting regulatory element driving gene expression in the zebrafish Pineal Gland
Bioinformatics, 2009Co-Authors: Shahar Alon, David C Klein, Reiko Toyama, Steven L Coon, Eli Eisenberg, Jasmine Jacobhirsch, Gideon Rechavi, Gad Vatine, Yoav GothilfAbstract:Motivation: The identification of functional cis-acting DNA regulatory elements is a crucial step towards understanding gene regulation. Ab initio motif detection algorithms have been extensively used in search of regulatory elements. Yet, their success in providing experimentally validated regulatory elements in vertebrates has been limited. Results: Here we report in silico identification and in vivo validation of regulatory elements that determine enhanced gene expression in the Pineal Gland of zebrafish. Microarray data enabled detection of genes that exhibit high expression in the Pineal Gland. The promoter regions of these genes were computationally analyzed in order to identify overrepresented motifs. The highest ranking motif identified is a CRX/OTX binding site, known to govern expression in the Pineal Gland and retina. The second highest ranking motif was not reported before; we experimentally validated its function in vivo by mutational analysis. The methodology presented here may be applicable as a general scheme for finding regulatory elements that contribute to tissue-specific gene expression. Contacts:yoavg@tauex.tau.ac.il; elieis@post.tau.ac.il Supplementary information: Supplementary data are available at Bioinformatics online.
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developmental and diurnal dynamics of pax4 expression in the mammalian Pineal Gland nocturnal down regulation is mediated by adrenergic cyclic adenosine 3 5 monophosphate signaling
Endocrinology, 2009Co-Authors: Martin F. Rath, Morten Møller, Steven L Coon, Michael J Bailey, Jongso Kim, Pascaline Gaildrat, David C KleinAbstract:Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the Pineal Gland. In this study we report that Pax4 is strongly expressed in the Pineal Gland and retina of the rat. Pineal Pax4 transcripts are low in the fetus and increase postnatally; Pax6 exhibits an inverse pattern of expression, being more strongly expressed in the fetus. In the adult the abundance of Pax4 mRNA exhibits a diurnal rhythm in the Pineal Gland with maximal levels occurring late during the light period. Sympathetic denervation of the Pineal Gland by superior cervical ganglionectomy prevents the nocturnal decrease in Pineal Pax4 mRNA. At night the Pineal Gland is adrenergically stimulated by release of norepinephrine from the sympathetic innervation; here, we found that treatment with adrenergic agonists suppresses Pineal Pax4 expression in vivo and in vitro. This suppression a...
Jorg H Stehle - One of the best experts on this subject based on the ideXlab platform.
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the mammalian Pineal Gland known facts unknown facets
Trends in Endocrinology and Metabolism, 2007Co-Authors: Erik Maronde, Jorg H StehleAbstract:In the mammalian Pineal Gland, information on environmental lighting conditions that is neuronally encoded by the retina is converted into nocturnally elevated synthesis of the hormone melatonin. Evolutionary pressure has changed the morphology of vertebrate Pinealocytes, eliminating direct photoreception and the endogenous clock function. Despite these changes, nocturnally elevated melatonin synthesis has remained a reliable indicator of time throughout evolution. In the photo-insensitive mammalian Pineal Gland this message of darkness depends on the master circadian pacemaker in the hypothalamic suprachiasmatic nuclei. The dramatic change in vertebrate Pinealocytes has received little attention; here, we therefore link the known evolutionary morphodynamics and well-investigated biochemical details responsible for rhythmic synthesis of melatonin with recently characterized patterns of gene expression in the Pineal Gland. We also address the enigmatic function of clockwork molecules in mammalian Pinealocytes.
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ontogeny of a diurnal rhythm in arylalkylamine n acetyltransferase mrna in rat Pineal Gland
Neuroscience Letters, 1998Co-Authors: Martina Pfeffer, Jorg H StehleAbstract:Melatonin synthesis in the Pineal Gland of adult rats is linked to cAMP-dependent transcriptional and post-transcriptional regulatory mechanisms affecting its rate-limiting enzyme, the arylalkylamine-N-acetyltransferase (AA-NAT). During development of the Pineal Gland, neuronal control gains access to the earlier matured cAMP-signaling pathway to shape the day-night rhythm in AA-NAT enzymatic activity. By semiquantitative in situ hybridization we analyzed if the developmental onset of a rhythmic AA-NAT activity is correlated to a temporally parallel onset in AA-NAT transcription. We found that AA-NAT mRNA levels in rat Pineal Gland become rhythmic at postnatal day 5. Thus, AA-NAT gene transcription in rat Pineal Gland starts to show day-night differences shortly prior to the appearance of a rhythmic AA-NAT activity.