Scientists show microRNA development role
role in the development of the fruit fly. The discovery means that
miRNA could emerge as a new target for interventions aimed at
treating disease, or as a therapeutic in its own right.
MicroRNA's are short strings of RNA that are made in large amounts in every cell from plant to humans. Scientists have recently found that microRNAs bind to messenger RNAs, which are the blueprints for proteins, and either target them for destruction or inhibit them from making proteins.
Research done by scientists at the Rockefeller University, involved systematically blocking each of the 46 known microRNAs that are active during early development of the fruit fly.
This is difficult to do by traditional genetic means, so they inject young fly embryos with short strings of RNA that bind to the microRNAs and prevent them from finding their target messenger RNAs. The researchers found that over half of the microRNAs were not only essential for development, but also affected it in very specific ways.
"Many of the fundamental processes in development are regulated by microRNAs," said Ulrike Gaul, head of the Laboratory for Developmental Neurogenetics. "This includes body patterning, morphogenesis, nervous system and muscle development. In particular, though, we found that cell survival relies very heavily on them."
Cell death in development is not uncommon. The developing embryo makes an overabundance of many cell types, like nerve cells, which it then removes later in a process of fine-tuning. In fact, the genes in flies that carry out a cell's death sentence, Hid, Grim and Reaper, are expressed in many healthy cells.
In mammals there are often multiple versions of the same miRNA genes, which makes them difficult to study by using gene deletion approaches, and conventional in situ hybridisation experiments are unreliable as miRNAs are too short to generate a signal.
Gaul's new research shows that it is microRNAs that stand between a cell's survival and its death at the hands of Hid, Grim and Reaper. The microRNAs bind to the messenger RNA of the death genes and prevent their proteins from being made. But when the microRNAs are blocked, Hid, Grim and Reaper proteins are produced, causing massive cell death and killing the fly embryo.
The microRNAs that block cell death all belong to the largest microRNA family in the fruit fly. The family is made up of 13 members, which are identical in sequence at one end but different at the other. There has been some debate on whether differences at this end are important, but Gaul's research now shows that they are central for helping the microRNAs find the right targets.
"Our findings show that while similar defects are seen when the different family members are blocked, they are not identical," Gaul said. "And we find that different family members interact differently with the three death genes."
By regulating which messenger RNAs are used to make protein, microRNAs can help cells react to an event without the nucleus being involved. For example, the ending of a nerve cell can be very far away from its nucleus. Localising and regulating messenger RNAs at the nerve endings enables the nerves to react very fast to an incoming signal, instead of every signal being transmitted to the nucleus and back.
Gaul said that the next experiments would look to further match up different microRNAs with their targets. In addition, he added that the concept of how microRNAs themselves are regulated was also a possible area of interest.
"We wanted to know if microRNAs were important and if they were specific, and we got those answers - they affect fundamental pathways and have a limited number of critical targets," said Gaul.
"Now we want to connect the microRNAs both to their upstream regulation and to their downstream targets to see where they fit in the developmental gene networks."