In 1989 Ambros established that lin-4 acts as a repressor of lin-14 activity. How lin-4 achieved this repression, however, was not known. In 1991, it was Ruvkun who established that genetic anomalies in lin-14's sequencespecifically in an area of the gene called the 3' untranslated region (3' UTR)were associated with excess production of the lin-14 protein produced from the messenger RNA that lin-4 targets.
A year later, Ambros successfully isolated and cloned lin-4. To his surprise, Ambros found that the gene's product was not a standard regulatory protein as he had expected, but a tiny non-protein-coding strand of RNA about 22 nucleotides long that is conserved in other nematode species.
Working together, Ambros and Ruvkun compared the lin-4 and lin-14 sequences and discovered that the 22-nucleotide lin-4 RNA and the 3' UTR were partially complementary and that the short complementary regions were highly conserved in evolutionary comparisons to other nematode lin-4 and lin-14 genes. They hypothesized that lin-4 RNA regulated lin-14 by binding to its 3' UTR sequences. Ruvkun then showed that lin-4 controlled the translation of the lin-14 mRNA into protein and it was through this channel that lin-4 achieved repression of lin-14.
Ambros and Ruvkun published back-to-back studies in Cell in 1993 that described these remarkable findings. The discovery, however, seemed more an oddity than a breakthrough at the time, in part because the lin-4 gene existed only in the worm.
The broader importance of the findingsthe idea that miRNAs might play a role in gene expression in other organismswas not immediately clear. Then, in 1999, Dr. Baulcombe, a British plant biologist, reported on his own groundbreaking discovery that a similar class of RNAs is involved in a related silencing process affecting viruses, transposable element
|Contact: Jim Fessenden|
University of Massachusetts Medical School