Retinoic Acid Signalling in the Pineal Gland Is Conserved Across Mammalian Species and Its Transcriptional Activity Is Inhibited by Melatonin

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Jan 21

PMID 36672220

Authors

Anna Ashton

Jason Clark

Julia Fedo

Angelo Sementilli

Yara D Fragoso

Peter McCaffery

Affiliations

Soon will be listed here.

Abstract

The pineal gland is integral to the circadian timing system due to its role in nightly melatonin production. Retinoic acid (RA) is a potent regulator of gene transcription and has previously been found to exhibit diurnal changes in synthesis and signalling in the rat pineal gland. This study investigated the potential for the interaction of these two systems. PCR was used to study gene expression in mouse and human pineal glands, ex-vivo organotypic cultured rat pineal gland and cell lines. The mouse and human pineal glands were both found to express the necessary components required for RA signalling. RA influences the circadian clock in the brain, therefore the short-term effect of RA on clock gene expression was determined in ex vivo rat pineal glands but was not found to rapidly regulate , , or . The interaction between RA and melatonin was also investigated and, unexpectedly, melatonin was found to suppress the induction of gene transcription by RA. This study demonstrates that pineal expression of the RA signalling system is conserved across mammalian species. There is no short-term regulation of the circadian clock but an inhibitory effect of melatonin on RA transcriptional activity was demonstrated, suggesting that there may be functional cross-talk between these systems.

References

Schrader M, Danielsson C, Wiesenberg I, Carlberg C . Identification of natural monomeric response elements of the nuclear receptor RZR/ROR. They also bind COUP-TF homodimers. J Biol Chem. 1996; 271(33):19732-6. DOI: 10.1074/jbc.271.33.19732. View

Ceinos R, Chansard M, Revel F, Calgari C, Miguez J, Simonneaux V . Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT. Neurosignals. 2005; 13(6):308-17. DOI: 10.1159/000081966. View

de The H, Tiollais P, Stunnenberg H, Dejean A . Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990; 343(6254):177-80. DOI: 10.1038/343177a0. View

Loudig O, Babichuk C, White J, Mueller C, Petkovich M . Cytochrome P450RAI(CYP26) promoter: a distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism. Mol Endocrinol. 2000; 14(9):1483-97. DOI: 10.1210/mend.14.9.0518. View

Davis K, Lazar M . Induction of retinoic acid receptor-beta by retinoic acid is cell specific. Endocrinology. 1993; 132(4):1469-74. DOI: 10.1210/endo.132.4.8384988. View

Nowfar S, Teplitzky S, Melancon K, Kiefer T, Cheng Q, Dwived P . Tumor prevention by 9-cis-retinoic acid in the N-nitroso-N-methylurea model of mammary carcinogenesis is potentiated by the pineal hormone melatonin. Breast Cancer Res Treat. 2002; 72(1):33-43. DOI: 10.1023/a:1014912919470. View

McNamara P, Seo S, Rudic R, Sehgal A, Chakravarti D, FitzGerald G . Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell. 2001; 105(7):877-89. DOI: 10.1016/s0092-8674(01)00401-9. View

Helfer G, Ross A, Russell L, Thomson L, Shearer K, Goodman T . Photoperiod regulates vitamin A and Wnt/β-catenin signaling in F344 rats. Endocrinology. 2012; 153(2):815-24. DOI: 10.1210/en.2011-1792. View

Bailey M, Coon S, Carter D, Humphries A, Kim J, Shi Q . Night/day changes in pineal expression of >600 genes: central role of adrenergic/cAMP signaling. J Biol Chem. 2008; 284(12):7606-22. PMC: 2658055. DOI: 10.1074/jbc.M808394200. View

10.

Namihira M, Honma S, Abe H, Tanahashi Y, Ikeda M, Honma K . Daily variation and light responsiveness of mammalian clock gene, Clock and BMAL1, transcripts in the pineal body and different areas of brain in rats. Neurosci Lett. 1999; 267(1):69-72. DOI: 10.1016/s0304-3940(99)00324-9. View

11.

Fukuhara C, Yamazaki S, Liang J . Pineal circadian clocks gate arylalkylamine N-acetyltransferase gene expression in the mouse pineal gland. J Neurochem. 2005; 93(1):156-62. DOI: 10.1111/j.1471-4159.2004.03008.x. View

12.

Dai J, Ram P, Yuan L, Spriggs L, Hill S . Transcriptional repression of RORalpha activity in human breast cancer cells by melatonin. Mol Cell Endocrinol. 2001; 176(1-2):111-20. DOI: 10.1016/s0303-7207(01)00449-x. View

13.

Golini R, Delgado S, Navigatore Fonzo L, Ponce I, Lacoste M, Anzulovich A . Daily patterns of clock and cognition-related factors are modified in the hippocampus of vitamin A-deficient rats. Hippocampus. 2012; 22(8):1720-32. PMC: 3382039. DOI: 10.1002/hipo.22007. View

14.

Ross A, Webster C, Mercer J, Moar K, Ebling F, Schuhler S . Photoperiodic regulation of hypothalamic retinoid signaling: association of retinoid X receptor gamma with body weight. Endocrinology. 2003; 145(1):13-20. DOI: 10.1210/en.2003-0838. View

15.

Ackermann K, Bux R, Rub U, Korf H, Kauert G, Stehle J . Characterization of human melatonin synthesis using autoptic pineal tissue. Endocrinology. 2006; 147(7):3235-42. DOI: 10.1210/en.2006-0043. View

16.

Maghsoodi B, Poon M, Nam C, Aoto J, Ting P, Chen L . Retinoic acid regulates RARalpha-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity. Proc Natl Acad Sci U S A. 2008; 105(41):16015-20. PMC: 2572971. DOI: 10.1073/pnas.0804801105. View

17.

Wongchitrat P, Felder-Schmittbuhl M, Govitrapong P, Phansuwan-Pujito P, Simonneaux V . A noradrenergic sensitive endogenous clock is present in the rat pineal gland. Neuroendocrinology. 2011; 94(1):75-83. DOI: 10.1159/000327430. View

18.

Lai L, Yuan L, Chen Q, Dong C, Mao L, Rowan B . The Galphai and Galphaq proteins mediate the effects of melatonin on steroid/thyroid hormone receptor transcriptional activity and breast cancer cell proliferation. J Pineal Res. 2008; 45(4):476-88. PMC: 4879591. DOI: 10.1111/j.1600-079X.2008.00620.x. View

19.

Kiefer T, Ram P, Yuan L, Hill S . Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat. 2002; 71(1):37-45. DOI: 10.1023/a:1013301408464. View

20.

Navigatore-Fonzo L, Golini R, Ponce I, Delgado S, Plateo-Pignatari M, Gimenez M . Retinoic acid receptors move in time with the clock in the hippocampus. Effect of a vitamin-A-deficient diet. J Nutr Biochem. 2012; 24(5):859-67. PMC: 3504648. DOI: 10.1016/j.jnutbio.2012.05.006. View