Understanding How Humans Adapt to Light/Dark Environments

Christopher Bradfield
University of Wisconsin

Background: Research into dioxin toxicology and the Ah receptor-ARNT signal transduction pathway has revealed a superfamily of proteins that appear to play central roles in how humans adapt to a number of different environmental stresses and stimuli. These factors, referred to as PAS proteins, appear to act as both sensors of environmental cues and transmitters of these signals to the nuclei of cells. The recent explosion in the number of known members of the PAS superfamily led to the discovery of sensors that are involved in responses to low atmospheric oxygen, tissue hypoxia, as well as exposure to polycyclic aromatic pollutants. A recent series of discoveries now appears to explain how organisms respond to the most fundamental environmental signals--day and night. In a flurry of recent papers, a number of laboratories used the dioxin signal transduction pathway to model the mechanism that underlies circadian rhythmicity in both mammals and Drosophila. Surprisingly, the basic transcriptional unit that drives these rhythms is a heterodimer of proteins called MOP3 and Clock. These heterodimers act in a manner that is strikingly similar to the Ah receptor-ARNT complex that mediates responses to polycyclic aromatic hydrocarbon and dioxin pollutants.

Advance:The discovery that circadian biology is regulated in a fashion similar to dioxin signal transduction recently gained additional support. These researchers at the University of Wisconsin and Northwestern University described a mouse model in which the gene encoding the MOP3 protein was knocked out. These MOP3 null animals were outwardly normal yet displayed a complete loss of circadian behavior. This work provides a molecular proof describing the core of the circadian cycle which is shared by many organisms.

Implication: These researchers have provided a simple animal model for use in better understanding circadian behavior and for screening drugs that might influence this biology. In addition to value in circadian rhythm biology, these mice also may be valuable in studies of depression and other disease states that are related to aberrant biological rhythms.

Citation: Bunger, MK, Wilsbacher, LD, Moran, SM, Clendenin, C, Radcliffe, LA, Hogenesch, JB, Simon, MC, Takahashi, JS, and Bradfield, CA (2000). Mop3 is an Essential Component of the Master Circadian Pacemaker in Mammals. Cell. 103:1009-1017