"No one had ever imagined that Lhx1 might be so intricately involved in SCN function," says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it's so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.
By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren't in sync with one another, despite appearing rhythmic individually.
"It was all about communicationthe neurons were not talking to each other without this molecule," says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.
Studying a mouse version of jet lagan 8-hour shift in their day-night cyclethe scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.
These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.
"This approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN," Panda says. "It can compensate for the loss of Lhx1."
On the other hand, cutting back on Vip could be another way to
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