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Homeobox genes and melatonin synthesis: regulatory roles of the cone-rod homeobox transcription factor in the rodent pineal gland.

Rohde K, Møller M, Rath MF - Biomed Res Int (2014)

Bottom Line: In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription.However, additional transcriptional control mechanisms exist.Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Rigshospitalet 6102, Blegdamsvej 9, 2100 Copenhagen, Denmark.

ABSTRACT
Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

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Appearance of Otx2, Crx, and Aanat transcripts in the developing rat pineal gland. Otx2 and Crx expression peak around birth [14], at which time Aanat expression is initiated [19]. The spatial and temporal correlation between peaks in expression of Otx2 and Crx and the start of Aanat expression supports that the OTX2 and CRX homeodomain transcription factors induce Aanat transcription [7]. E, embryonic day; P, postnatal day.
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fig1: Appearance of Otx2, Crx, and Aanat transcripts in the developing rat pineal gland. Otx2 and Crx expression peak around birth [14], at which time Aanat expression is initiated [19]. The spatial and temporal correlation between peaks in expression of Otx2 and Crx and the start of Aanat expression supports that the OTX2 and CRX homeodomain transcription factors induce Aanat transcription [7]. E, embryonic day; P, postnatal day.

Mentions: The mammalian pineal gland develops as a dorsal evagination from the most caudal part of the diencephalic roof [9]. As in other parts of the brain, timely and spatially controlled expression of a specific set of homeobox genes is essential for development of the pineal gland [7]. Gene knockout studies have identified a limited number of homeobox genes that are required for normal development of the rodent pineal gland; these include orthodenticle homeobox 2 (Otx2) [10], paired box 6 (Pax6) [11], brain specific homeobox (Bsx) [12], and LIM homeobox 9 (Lhx9) [13]. In line with a role of this set of homeobox genes in the immature developing pinealocyte, that is, the principal melatonin-producing cell type of the pineal gland, in situ hybridization analyses have revealed that these homeobox genes are highly expressed during early stages in rodent pineal gland development before the appearance of pineal melatonin synthesis [13–17]. However, pineal expression of homeobox genes is not restricted to prenatal stages (Figure 1); expression of homeobox genes involved in pineal development may persist into adulthood (e.g., Otx2) [14], expression may start at perinatal stages just prior to the onset of melatonin synthesis (e.g., Crx and retina and anterior neural fold homeobox (Rax)) [14, 18], or expression levels may start to increase even after or concomitant with the ontogenetic onset of melatonin synthesis (e.g., Pax4 and Lhx4) [13, 15]. Thus, another set of homeobox genes, including Crx, predominantly exert their function in the mature melatonin-producing pinealocyte.


Homeobox genes and melatonin synthesis: regulatory roles of the cone-rod homeobox transcription factor in the rodent pineal gland.

Rohde K, Møller M, Rath MF - Biomed Res Int (2014)

Appearance of Otx2, Crx, and Aanat transcripts in the developing rat pineal gland. Otx2 and Crx expression peak around birth [14], at which time Aanat expression is initiated [19]. The spatial and temporal correlation between peaks in expression of Otx2 and Crx and the start of Aanat expression supports that the OTX2 and CRX homeodomain transcription factors induce Aanat transcription [7]. E, embryonic day; P, postnatal day.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4022116&req=5

fig1: Appearance of Otx2, Crx, and Aanat transcripts in the developing rat pineal gland. Otx2 and Crx expression peak around birth [14], at which time Aanat expression is initiated [19]. The spatial and temporal correlation between peaks in expression of Otx2 and Crx and the start of Aanat expression supports that the OTX2 and CRX homeodomain transcription factors induce Aanat transcription [7]. E, embryonic day; P, postnatal day.
Mentions: The mammalian pineal gland develops as a dorsal evagination from the most caudal part of the diencephalic roof [9]. As in other parts of the brain, timely and spatially controlled expression of a specific set of homeobox genes is essential for development of the pineal gland [7]. Gene knockout studies have identified a limited number of homeobox genes that are required for normal development of the rodent pineal gland; these include orthodenticle homeobox 2 (Otx2) [10], paired box 6 (Pax6) [11], brain specific homeobox (Bsx) [12], and LIM homeobox 9 (Lhx9) [13]. In line with a role of this set of homeobox genes in the immature developing pinealocyte, that is, the principal melatonin-producing cell type of the pineal gland, in situ hybridization analyses have revealed that these homeobox genes are highly expressed during early stages in rodent pineal gland development before the appearance of pineal melatonin synthesis [13–17]. However, pineal expression of homeobox genes is not restricted to prenatal stages (Figure 1); expression of homeobox genes involved in pineal development may persist into adulthood (e.g., Otx2) [14], expression may start at perinatal stages just prior to the onset of melatonin synthesis (e.g., Crx and retina and anterior neural fold homeobox (Rax)) [14, 18], or expression levels may start to increase even after or concomitant with the ontogenetic onset of melatonin synthesis (e.g., Pax4 and Lhx4) [13, 15]. Thus, another set of homeobox genes, including Crx, predominantly exert their function in the mature melatonin-producing pinealocyte.

Bottom Line: In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription.However, additional transcriptional control mechanisms exist.Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Rigshospitalet 6102, Blegdamsvej 9, 2100 Copenhagen, Denmark.

ABSTRACT
Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

Show MeSH