The Flick of a Switch
Rora is a gene that produces a transcription factor -- a type of regulatory protein that binds to DNA and can turn gene expression on or off like the flicking of a switch.
Rora, once it is turned on, activates the transcription of a gene that encodes another transcription activator known as Bmal-1, which is one of the known circadian genes. Bmal-1 drives the transcription of a protein called cryptochrome, which subsequently inhibits the ability of Bmal-1 to activate cryptochrome's own transcription. This feedback loop is what keeps the body entrained to a 24-hour day.
Since Bmal-1 is so crucial to keeping the body's clock entrained, finding something like Rora, which alters Bmal-1's expression, is significant and suggests that Rora is also part of the mammalian clock. But the scientists wanted to go further and prove that Rora protein plays a role in the circadian rhythms inside a living creature.
They observed a mutant murine model that has a defective Rora gene. This murine model is called "staggerer" because its genetic defect causes a characteristic loss of coordination.
As it turns out, the staggerer model with a defective Rora gene also has a defect in its ability to regulate its circadian clock. The team of researchers showed that staggerers have aberrant circadian rhythyms and a shortened clock that is only 23.2 hours long. This situation is sort of like a grandfather clock that cannot keep good time and runs too fast because it has a faulty spring balance.
"What we are showing is that circadian clocks are composed of interlocking feedback loops," says Kay. The overlapping feedback, says Kay, is probably there for a number of reasons. It makes the clock more robust and resilient to change. It means that there is more than one cycle in which changes to clock genes can affect changes to other genes, and therefore the clock can be reset more easily.
Contact: Keith McKeown
Scripps Research Institute