Nordic Life Science 1
PHYSIOLOGY OR MEDICINE // MICRORNA “This unexpect
ed layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life.” T HROUGHOUT THEIR CAREERS, the two Nobel laureates, Professor Victor Ambros, University of Massachusetts Medical School, Worcester, and Professor Gary Ruvkun, Massachusetts General Hospital, Boston, Harvard Medical School, have shared a common interest in understanding how different cell types develop – and together they discovered a completely new principle of gene regulation, mediated by microRNAs. In a nutshell, microRNAs are snippets of genetic material that can turn genes off. Scientists previously believed that only proteins could do this, and in the 1960s it was shown that specialized proteins, transcription factors, controlled the flow of genetic information by determining which mRNAs are produced. However, findings by the two laureates published in Cell 1993 would change this fact. “Whereas proteins in the nucleus regulate RNA transcription and splicing, microRNAs control the translation and degradation of mRNA in the cytoplasm. This unexpected layer of post-transcriptional gene regulation has critical importance throughout animal development and in adult cell types, and is essential for complex multicellular life,” states Rickard Sandberg, Professor at the Department of Cell and Molecular Biology at Karolinska Institutet, and Member of the Nobel Assembly at Karolinska Institutet. From C. elegans to humans In the 1980s the two laureates, as postdoctoral fellows in the Robert Horvitz lab, were studying the roundworm C. elegans to better understand the genes that control the timing of activation of different genetic programs. Ambros studied one mutant roundworm, lin-4, that could not advance past a particular developmental stage. He sought out to identify the gene altered in the lin-4 worms. Methodical mapping allowed the cloning of the gene and led to the finding that the lin-4 gene produced an unusually short RNA molecule that lacked a code for protein production. “This was a surprising discovery of a tiny non-coding RNA that could regulate mRNA translation and degradation through basepairing with sequences in mRNA untranslated regions. He discovered the first microRNA,” says Sandberg. Ambros' results suggested that this small RNA from lin4 was responsible for inhibiting a gene called lin-14 gene, but it was still unknown how this worked. D uring the same period of time, Ruvkun had investigated the regulation of the lin-14 gene and he demonstrated that the critical region for lin-4’s effect is in the UTR (untranslated region). Upon sharing the information, they discovered that the microRNA directly base-paired with the mRNA. In 2000 Ruvkun’s research group also published the discovery of another microRNA. When the second microRNA was discovered and also found to be highly conserved across the animal kingdom, it spurred lots of cloning activities and soon it was realized that microRNAs are prevalent across multicellular organisms, with a subset being highly conserved across evolution. Beautiful as it is Today, thanks to Ambros’ and Ruvkun’s discoveries, we know the human genome codes for over one thousand microRNAs, and advances are being made in developing microRNA-based diagnostics and therapeutics for diseases. Abnormal regulation by microRNA can contribute to cancer, and mutations in genes coding for microRNAs have been found in humans, causing conditions such as congenital hearing loss, and eye and skeletal disorders. NORDICLIFESCIENCE.ORG | 35