Since the circadian oscillatory network has three components (SCN, entrainment, and tissue oscillators), what is the basic SCN organization and the basic molecular mechanisms of the circadian clock systems?
The SCN cytoarchitecture reveals functional organization. In mammals, the SCN comprises some 100,000 neurons and is divided into a primarily light-sensitive SCN core , which receives the unique nonimage retinal signaling RGC/RHT, and a SCN shell , which is capable of generating rhythms. As will now be discussed, these central and peripheral circadian oscillations have very similar genetic processes. The nuclear mechanisms controlling these circadian rhythms will now be discussed. Modern laboratory techniques in tissue cultures and genetics are allowing for real-time monitoring of circadian rhythms. The transcriptional and translational processes interact in feedback loop relationships, constantly running in nearly every cell of the body, and are regulated to a 24-hour cycle with periods of activity and quiescence. Importantly, if SCN cells are removed from the body or are placed in complete darkness, they are still capable of maintaining a 24-hour period of activity despite the absence of an external LD cue. This molecular clockwork, as the experts call it, has two primary positive loop genes, circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1). Usually, at the start of the day, these two proteins, CLOCK and BMAL1, will noncovalently join (heterodimerize) and, through a complicated series of events, this heterodimer will activate transcription of negative feedback signals. These negative loop components typically are periodic circadian protein (PER1 and PER2) and cryptochrome (CRY1 and CRY2). The PER and CRY proteins, in turn, heterodimerize and repress BMAL1–CLOCK activity. The nuclear receptors Rev-erb alpha/beta and ROR alpha/beta are also involved in control and stabilization of this system because they act as transcriptional repressors and activators, respectively, of BMAL1. Up to 10–50% of all genes expressed in a given tissue use this same genetic method of regulation; specifically included are the regulation of transcription, translation, and messenger ribonucleic acid (mRNA) processing (formation, degradation, micro-turnover, and splicing). The oscillations are independent of retinal input, and destruction of the SCN abolishes oscillations with significant downstream influence (e.g. certain behaviors, such as drinking and movement; and hormonal rhythms, such as cortisol).