Although the how of a gene’s function is important, the when, too, is crucial. The ebb and flow of gene expression can influence a cell’s fate during development, the maturation of entire organisms, and even the evolution of species—helping to explain how species with very similar gene content can differ so dramatically.

Nature’s developmental clockwork, however, is exceedingly complex. It depends on the activation or repression of a specific and unique complement of genes. And these genes, in turn, are regulated by microRNA molecules. And, finally, the microRNAs are also subject to regulation. Thus, to understand nature’s clockwork, one must study the regulators of the regulators of the regulators.

Little is known of the ultimate regulators—the elements that determine the activities of microRNAs. These elements, however, are presumably as subtle as they are powerful—subtle because microRNAs defined temporal gene expression and cell lineage patterns in a dosage-dependent manner; powerful because a single microRNA gene can control hundreds of other genes at once. And, as always, timing is everything: If a microRNA turns off genes too early or too late, the organism that depends on them will likely suffer severe developmental defects.

To undertake a search for genes that control developmental timing through microRNAs, a team of researchers at Cold Spring Harbor Laboratory relied on a tried-and-true model of animal development, Caenorhabditis elegans. These worms have a fixed number of cells, and each cell division is precisely timed. “It is the perfect model for our work,” said team leader Christopher Hammell, Ph.D. “It enables us to understand exactly how a mutation affects development, whether maturation is precocious or delayed, by directly observing defects in the timing of gene expression.”

The researchers described their work in an article entitled, “LIN-42, the Caenorhabditis elegans PERIOD homolog, Negatively Regulates MicroRNA Transcription,” which appeared July 17 in PLoS Genetics.

“With the goal of unveiling factors that regulate the expression of microRNAs that control developmental timing, we identified LIN-42, the C. elegans homolog of the human and Drosophila period gene implicated in circadian gene regulation, as a negative regulator of microRNA expression,” the authors wrote. “By analyzing the transcriptional expression patterns of representative microRNAs, we found that the transcription of many microRNAs is normally highly dynamic and coupled aspects of post-embryonic growth and behavior.”

“LIN-42 shares a significant amount of similarity to the genes that control circadian rhythms in organisms such as mice and humans,” explained Roberto Perales, Ph.D., one of the lead authors of the study. “These are genes that control the timing of cellular processes on a daily basis for you and me. In the worm, these same genes and mechanisms control development, growth, and behavior. This system will provide us with leverage to understand how all of these things are coordinated.”

In short, the researchers found that LIN-42 controls the repression of numerous genes in addition to microRNAs. They also discovered that levels of the protein encoded by LIN-42 tend to oscillate over the course of development and form a part of a developmental clock.

“LIN-42 provides the organism with a kind of cadence or temporal memory, so that it can remember that it has completed one developmental step before it moves on to the next,” emphasized Dr. Hammell. “This way, LIN-42 coordinates optimal levels of the genes required throughout development.”

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