Cloning of mouse BMAL2 and its daily expression profile in the suprachiasmatic nucleus: a remarkable acceleration of Bmal2 sequence divergence after Bmal gene duplication

doi:10.1016/S0304-3940(01)01581-6

Neuroscience Letters

Volume 300, Issue 2, 9 March 2001, Pages 111-114

https://doi.org/10.1016/S0304-3940(01)01581-6 Get rights and content

Abstract

Brain-Muscle-Arnt-Like-protein 2 (BMAL2; Arnt4) (aryl hydrocarbon receptor nuclear translocator) is a recently identified basic Helix-Loop-Helix-Per-Arnt-Sim (bHLH-PAS) transcription factor, which contributes to a positive regulation of autoregulatory feedback loop in vertebrate circadian clock systems. In this study, we cloned cDNAs encoding mouse and rat BMAL2 (mBMAL2 and rBMAL2) from mouse midbrain and rat-1 fibroblast cells, respectively. A phylogenetic analysis strongly suggested that vertebrate Bmal1 and Bmal2 genes were generated by a single gene duplication of an ancestral Bmal gene, a vertebrate ortholog of dCyc gene, and that ‘BMAL2’s putatively termed so far are orthologous. Interestingly, BMAL2 proteins have diverged about 20-fold more rapidly than BMAL1 proteins after the duplication, suggesting an as-yet-unidentified function conserved in BMAL1 but not in BMAL2. mBmal2 mRNA was constitutively expressed throughout the day under light–dark cycle in the mouse hypothalamus containing suprachiasmatic nucleus, the site of the central circadian oscillator in mammals.

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Acknowledgements

We thank Dr Daisuke Kojima for help in constructing phylogenetic tree, Dr Kimiko Shimizu for technical advice and Takaoki Kasahara and Tsuyoshi Hirota for technical assistance. This work was supported in part by Grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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The PAS (PER, ARNT, SIM) protein family plays a vital role in mammalian biology and human disease. This analysis arose from an interest in the signaling mechanics by the Ah receptor (AHR) and the Ah receptor nuclear translocator (ARNT). After more than fifty years by studying this and related mammalian sensor systems, describing the role of PAS domains in signal transduction is still challenging. In this perspective, we attempt to interpret recent studies of mammalian PAS protein structure and consider how this new insight might explain how these domains are employed in human signal transduction with an eye towards developing strategies to target and engineer these molecules for a new generation of therapeutics. Our approach is to integrate our understanding of PAS protein history, cell biology, and molecular biology with recent structural discoveries to help explain the mechanics of mammalian PAS protein signaling. As a learning set, we focus on sequences and crystal structures of mammalian PAS protein dimers that can be visualized using readily available software.
Effect of monochromatic light on the circadian clock of cultured chick retinal tissue
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Citation Excerpt :
The results of present study showed that the arrhythmic expression of cBmal2 did not affect the circadian rhythm of negative-regulating clock genes, cAanat or melatonin secretion of retina tissue. In addition, the temporal profile of Bmal2 in mammal SCN was arrhythmic (Okano et al., 2001), which indicated that cBmal2 is an unnecessary positive element. Previous study showed that Cry2 had arrhythmic expression pattern in vivo retina of chick (Bailey et al., 2004) and redheaded bunting (Singh et al., 2013).
The central biological clock system of bird is formed by hypothalamus suprachiasmatic nucleus, pineal gland and retina thereby interacting with each other in a neuroendocrine loop. Previous results have confirmed that monochromatic light can influence the clock genes in the pineal gland, hypothalamus and retina of chicks in vivo. The present work was conducted to study whether the cultured retinal tissue of chick could maintain the circadian oscillation and whether the monochromatic light affect the expression level of cultured retinal circadian clock in vitro. Retinal tissues of 0-day-old chicks were cultured in vitro under 4 light treatments (white, red, green and blue lights) with light dark cycle 12:12 and constant dark. The tissues and culture medium were collected every each 4 h. Melanopsin, clock genes, cAanat, the positive-regulating clock proteins and melatonin were measured. The results showed that cOpn4-1, cOpn4-2, cBmal1, cCry1, cPer2, cPer3, cAanat and melatonin concentrations possessed a significant circadian rhythm in cultured chick retina tissues under different monochromatic lights; while, in constant dark, cBmal1, cCry1, cPer2, cPer3, cAanat and melatonin concentration possessed a significant circadian rhythm. Green light promoted the circadian expression level of cOpn4-1, cOpn4-2, cBmal1, cAanat and BMAL1 proteins and the circadian rhythm of melatonin secretion of retina by increasing the mesors and amplitudes. In addition, green light significantly increased the average expression levels of cClock, cBmal2 and CLOCK proteins which were expressed arrhythmically. Results suggested that the retina is a central oscillator with autonomous circadian rhythm. In isolated retina tissues, green light activated the expression of melanopsin and promoted the expression of positive-regulating clock genes, thereby up-regulating the expression of cAanat and resulting the increasing of the synthesis and secretion of melatonin.
Decreased expression of Bmal2 in patients with Parkinson's disease
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Bmal1 is one of the central regulators of the clock machinery. Recently, we examined the expression profile of Bmal1 in total leukocytes for a 12 h duration during the evening, overnight, and the morning, in subjects with Parkinson's disease (PD) and healthy controls. The results indicate that the expression of Bmal1 is significantly lower in PD patients versus control subjects. However, it is still unclear whether other key regulators of the clock machinery, especially Bmal2, the paralog of Bmal1, are also expressed differently in PD. To address this issue, the expression profiles of Bmal2, Clock, and Dec1 were examined in the same samples using real-time RT-PCR assay. The results show a difference in the expression pattern of Bmal2, but not Clock and Dec1. The expression of Bmal2 is significantly lower in PD at 21:00 h (p = 0.005) and 00:00 h (p = 0.025). These results together with our previous findings suggest that the molecular clock in total leukocytes is disturbed in PD patients.
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The aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1β) is a bHLH/PAS family member that acts as a dimerization partner in several distinct signal transduction pathways. ARNT dimerizes with a variety of bHLH/PAS proteins such as the aryl hydrocarbon receptor (AHR), the hypoxia-inducible factor 1 family (HIF-1α, HIF-2α, HIF-3α), the single-minded proteins (SIM1, SIM2), or ARNT itself; however, each dimeric complex associates with distinct cis-acting DNA elements to regulate genes. Thus, ARNT is considered a master regulator required for response to hypoxia, angiogenesis, xenobiotics, and in various developmental pathways. Importantly, several other isoforms of ARNT have been identified in mammalian and aquatic species including ARNT2, ARNT3 (BMAL1, MOP3, JAP3, ARNTL1, TIC), and ARNT4 (BMAL2, MOP9, ARNTL2, CLIF). Although many of the interactions of ARNT have been established both in vitro and in vivo, the interactions of other ARNT isoforms are less clear. The goal of this chapter is to provide a comprehensive overview of each ARNT isoform. Emphasis is placed on ARNT protein structure, tissue expression, function in various signal transduction pathways, and cross talk of various pathways through ARNT.
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The aryl hydrocarbon receptor is a signal regulated transcription factor that has best been characterised as regulating the xenobiotic response to a variety of planar aromatic hydrocarbons. There is compelling evidence that it mediates most, if not all, of the toxic effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). Dioxin exposure results in a wide variety of toxic outcomes including severe wasting syndrome, chloracne, thymic involution, severe immune suppression, reduced fertility, hepatotoxicity, teratogenicity, tumour promotion and death. The pleiotropy of toxic outcomes implies the disruption of a wide range of normal physiological functions. The aryl hydrocarbon receptor has developmentally restricted expression as well as developmental defects in gene-targeted mice. It has a wide range of target genes that do not fit into the classical xenobiotic metabolising gene battery and has recently been shown to interact with NF-kappa B and the estrogen receptor. There is also evidence for its activation in the absence of exogenous ligand, all of which point to various roles outside xenobiotic metabolism. Ligands so far identified display differential activation potential with respect to receptor activity. This article addresses activities of the aryl hydrocarbon receptor that are outside the xenobiotic response. Known physiological roles are discussed as well as how their disruption contributes to the pleiotropic toxicity of TCDD.

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¹: These authors contributed equally to this work.

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Neuroscience Letters

Abstract

Section snippets

Acknowledgements

References (20)

A serum shock induces circadian gene expression in mammalian tissue culture cells

Cell

cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage

Biochem. Biophys. Res. Commun.

cDNA cloning of a novel bHLH-PAS transcription factor superfamily gene, BMAL2: its mRNA expression, subcellular distribution, and chromosomal localization

Biochem. Biophys. Res. Commun.

A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock

Cell

CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression

J. Biol. Chem.

Transcriptionally active heterodimer formation of an Arnt-like protein, Arnt3, with HIF-1α, HLF, and Clock

Biochem. Biophys. Res. Commun.

MOLPHY: programs for molecular phylogenetics based on maximum likelihood, Version 2.3

Asynchronous oscillations of two zebrafish CLOCK partners reveal differential clock control and function

Proc. Natl. Acad. Sci. USA

PHYLIP, Version 3.572

Role of the CLOCK protein in the mammalian circadian mechanism

Science

Cited by (41)

Dimerization Rules of Mammalian PAS Proteins

Effect of monochromatic light on the circadian clock of cultured chick retinal tissue

Decreased expression of Bmal2 in patients with Parkinson's disease

The daily rhythm of mice

ARNT: A Key bHLH/PAS Regulatory Protein Across Multiple Pathways

The pleiotropy of dioxin toxicity - Xenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles