Clock Genes in Glia Cells

Abstract

FULL IN DESK___ Clock Genes in Glia Cells: A Rhythmic History Donají Chi-Castañeda, Arturo OrtegaFirst Published September 25, 2016 Review Article https://doi.org/10.1177/1759091416670766 Article information Open Access Creative Commons Attribution 3.0 License Abstract Circadian rhythms are periodic patterns in biological processes that allow the organisms to anticipate changes in the environment. These rhythms are driven by the suprachiasmatic nucleus (SCN), the master circadian clock in vertebrates. At a molecular level, circadian rhythms are regulated by the so-called clock genes, which oscillate in a periodic manner. The protein products of clock genes are transcription factors that control their own and other genes’ transcription, collectively known as “clock-controlled genes.” Several brain regions other than the SCN express circadian rhythms of clock genes, including the amygdala, the olfactory bulb, the retina, and the cerebellum. Glia cells in these structures are expected to participate in rhythmicity. However, only certain types of glia cells may be called “glial clocks,” since they express PER-based circadian oscillators, which depend of the SCN for their synchronization. This contribution summarizes the current information about clock genes in glia cells, their plausible role as oscillators and their medical implications. Keywords circadian rhythms, clock genes, glia cells, oscillators, rhythmicity, suprachiasmatic nucleus Introduction Most light-sensitive organisms have built-on time-measuring devices that are commonly known as circadian clocks. These structures allow them to anticipate day time and hence to organize their behavior as well as physiological and biochemical processes in a proactive manner. Circadian rhythms are generated endogenously through genetic control (King and Takahashi, 2000) in living systems, ranging from bacteria to humans (Harmer et al., 2001; Bell-Pedersen et al., 2005); and control vital aspects of the organism physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. At the center of these rhythms resides the circadian clock machinery, an amazingly transcription-translation feedback system regulated by a group of genes that oscillate in a circadian manner, the so-called clock genes. The circadian system is hierarchically organized, meaning that while molecular oscillations occur in most cells and tissues of the body, the suprachiasmatic nucleus (SCN) functions as the master regulator to synchronize the phase of the other oscillating tissues (Schibler and Sassone-Corsi, 2002; Hastings et al., 2008). Although the general consensus of the cellular identity of oscillating cells in the brain point to neurons, glia cells of different brain areas have been proposed to act as circadian oscillators that are dependent on the SCN for their synchronization (Siwicki et al., 1988; Zerr et al., 1990; Ewer et al., 1992). Nevertheless, despite of the fact that glia cells have a pivotal role in most of the central nervous system (CNS) functions, their role in circadian physiology is only begging to be understood. With this in mind, we discuss here the recent knowledge about clock genes in glia cells, their plausible role as cellular oscillators, and their involvement in pathological conditions. Circadian Rhythms The term circadian was introduced by Halberg to describe the biological rhythms that have a period of approximately 24 h, namely the circadian rhythms (from the Latin circa, “around,” and dies, “day,” meaning literally “about a day”; Halberg, 1959). Circadian rhythms are found in every kingdom of life, and in mammals, regulate a plethora of functions in the organism, including the rest-activity cycle, daily variations in metabolism and body temperature, and the rhythmic secretion of hormones (Stratmann and Schibler, 2006). In higher vertebrates, circadian oscillators exist in the brain as well as in other organs or tissues (Tosini and Menaker, 1996; Granados-Fuentes et al., 2006). The “master clock” that coordinates the activities of other oscillators resides in the SCN, which is located in the anterior hypothalamus and is comprised of a heterogeneous population of neurons and relatively understudied glia. Circadian oscillators in other brain areas or tissues are called “peripheral clocks” and are under the influence of the SCN, presumably through combination of neural and humoral signaling (Balsalobre et al., 2000; Cheng et al., 2002; Schibler and Sassone-Corsi, 2002; Chung et al., 2011). The SCN receives photic information from the environment via neurons transcending from the retina through the retino-hypothalamic tract (Moore and Lenn, 1972), which allows the setting of SCN circadian oscillators to external light cues (Johnson et al., 1988). Particularly, the surgical ablation of the SCN in mammals causes animals to become arrhythmic in locomotor activities, endocrine output, and other biochemical and physiological processes (Moore and Eichler, 1972; Stephan and Zucker, 1972; Turek, 1985). Transplantation of SCN tissue to SCN-lesioned animals restores circadian rhythms with the period of the donor (Ralph et al., 1990; Sujino et al., 2003). When isolated in vitro, the SCN continues to express circadian rhythms in glucose metabolism, gene expression, and electrical activity similar to the in vivo scenario (Green and Gillete, 1982; Herzog et al., 1997; Yamazaki et al., 2000). Molecular Machinery of Circadian Clocks The molecular mechanism that generates circadian rhythms involves the interaction positive and negative feedback loops of transcriptional or translational processes of clock genes (Dunlap, 1999; Harmer et al., 2001; Reppert and Weaver, 2001). In mammals, two basic helix-loop-helix transcription factors, Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator-Like Protein 1 (BMAL1), heterodimerize and subsequently bind to conserved E-box sequences in target gene promoters. In this manner, this complex controls the rhythmic expression of mammalian Period (Per1, Per2, Per3) and Cryptochrome (Cry1, Cry2) genes (Dunlap, 1999; Reppert and Weaver, 2001). If the concentration of these proteins is large enough, they dimerize and inhibit transcription of the genes Per1 y Per2 interacting with CLOCK and BMAL1. The positive feedback loop is mediated PER2, regulating Bmal1 transcription; BMAL1 promotes heterodimerization of CLOCK:BMAL1, so that transcription cycles Per/Cry can be restarted (Dunlap, 1999; Harmer et al., 2001; Reppert and Weaver, 2001; Okamura et al., 2002). Another regulatory loop is mediated by the orphan nuclear receptors, the Retinoic Acid Receptor-Related Orphan Receptor α/β/γ (ROR α/β/γ) and the Reverse Erb α/β (Rev-erb α/β), that are responsible to activate and inhibit, respectively, transcription of Bmal1 through the retinoic acid Receptor Response Element (RRE) in its promoter, leading it to oscillate in a circadian manner (Figure 1; Preitner et al., 2002; Sato et al., 2004; Akashi and Takumi, 2005; Guillaumond et al., 2005).