Deficiencies in micro-RNA molecules

 From the symptoms accompanying the deficiency of the gene, it is possible to deduce the function of the normal gene. However, until now scientists have not extensively used this method in deciphering the role of microRNAs, those tiny RNA molecules, whose role is to control genes. Now, in the first report on the effects of missing a single microRNA in vertebrates, scientists describe mice with cardiac abnormalities

Geneticists often point out that the way to test how a gene works is to make it deficient and then see what happens as a result of that deficient. From the symptoms accompanying the deficiency of the gene, it is possible to deduce the function of the normal gene. However, until now scientists have not extensively used this method in deciphering the role of microRNAs, those tiny RNA molecules, whose role is to control genes. Now, in the first report on the effects of missing a single microRNA in vertebrates, scientists describe mice with cardiac abnormalities.
MicroRNA molecules were first discovered in the 90s of the last century. These molecules were found to control a quarter or more of the human genome. These molecules can stop or activate the production of certain proteins and may play a role in cancer and early developmental processes.
MicroRNA molecules exist naturally in plant and animal cells. It is a normal RNA sequence, which goes through a series of cuts until it reaches a tiny size of 21-25 nucleotides. The DNA in the nucleus is copied into a messenger RNA molecule that leaves the nucleus and is translated into a protein on a ribosome. The microRNA molecules prevent the process by attaching to the target messenger RNA. In animals, there is a partial match between the target and the microRNA, the partial attachment between them inhibits the binding of the messenger RNA to the ribosome, so it does not translate and the protein is not formed. In this way, the cell has fast, flexible and reversible control over the production of proteins. The RNA of the target gene is produced in excess, while the microRNA enables fine-tuning to the desired level for real activity.
Due to the importance of the microRNA system for controlling gene expression, when it does not function properly it has harmful effects on processes in the cell. Abnormal expression of microRNA has already been discovered in various types of cancer. Biotechnology companies are struggling to discover how microRNA can be used as a treatment for various diseases, for example as a way to prevent the expression of certain genes or the activation of other genes.
Last year, developmental biologist Eric Olson of the University of Texas and his colleagues reported that they had identified about a dozen different microRNAs as cardiac regulators (of activation or closure) in the mouse heart and in some cases in the human heart. However, it was not clear what the roles of the individual microRNAs were.
Olsson and Van Rooij began to examine a specific microRNA whose sequence is identical to a part of one of the genes. This gene, alpha-myosin-heavy-chain, is mainly expressed in cardiac muscle cells. The researchers wanted to test how the lack of that part of the gene that codes for the specific microRNA, called miR-208, would affect mice that, as a result of missing that section of the gene, would be without any microRNA of the mir-208 type.
At first, it seemed to have no significant effect. "We received mice that seemed healthy to us, and we had to try to understand what was wrong with them," says Olson. The group tested this by applying stress conditions to the hearts of the mice. The stress conditions simulated arteriosclerosis, and thyroid signals were also blocked, thereby applying additional stress conditions to the organ. When they did so, the researchers discovered the defect: the hearts failed to activate a gene related to the alpha-myosin-heavy-chain gene, a gene called beta-myosin-heavy-chain, which is normally activated when the heart is under stress conditions (distress).
Instead, the protein levels of the alpha version of the gene increased, suggesting that one gene is compensating for silencing the other gene, the team of researchers reports in the journal Science. These findings suggest that the normal function of microRNA miR-208 is to adjust to the beta version of the gene and enable its expression. It is not clear, the researchers say, how this on-off switch affects the animal's health, but they believe that mir-208 helps control the heart's response to stressful conditions.
Furthermore, in heart tissue from these mice, researchers found several genes that were activated in the tissue, but usually are not activated in heart muscle cells but only in skeletal muscle cells. These findings indicate that it is possible that the miR-208 microRNA may ensure proper development of heart muscle cells, says van Rooij.
Scott Hammond, a molecular biologist from the University of North Carolina, says that he was very impressed by the precise effects of the microRNA: "The phenomenon of abnormality occurs only in adults; Only under certain strict conditions". Hammond and other researchers anticipate that much more information will be discovered about the relationship between microRNAs and various diseases.

 
http://sciencenow.sciencemag.org/cgi/content/full/2007/323/3
http://stwww.weizmann.ac.il/G-Bio/news/20-1-05.doc