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    Cells do not fool around


    What needs to happen to enable stem cells to differentiate into mature cells? This question is preoccupying researchers worldwide. Scientists from the University of Würzburg’s Biocenter have now shed light on important aspects of this complex phenomenon. They have come across a new form of gene regulation.

    Neural stem cells carry information in their genetic material that the cells need to develop into mature nerve cells. To stop these genes from being activated at the wrong time, however, other molecules make sure that they remain repressed. In the case of neural stem cells, this is a protein structure known as the REST complex.

    There are various ways of achieving this repression: firstly, the cell can be prevented from even reading the information present on the DNA strand; alternatively, the information is read and then leaves the cell nucleus as so-called mRNA. But before the cell can use this to create a protein that regulates the differentiation process, another player enters the action and prevents protein synthesis – so-called microRNA.

    Research at the Department of Biochemistry

    Whether we are talking mRNAs, microRNAs or other forms, versatile RNA molecules are the focus of research at the University of Würzburg’s Department of Biochemistry. Here, Professor Utz Fischer and his colleagues are examining complex processes in cells using zebrafish and mouse cells as specimens. Their most recent finding is reported on in the latest issue of the journal Genes & Development. The discovery was even deemed by the publishers to be worthy of its own overview report.

    Fischer and his colleagues Holger Dill, Bastian Linder, and Alexander Fehr have examined which processes are running when a stem cell transforms into a nerve cell. For this to happen, the activity of the REST complex has to be repressed first. Only then can the genetic information that is required for differentiation be read to start the process. The scientists came across a control loop with surprisingly few parties involved.

    An interplay of activation and repression

    In this case, the gene in the genetic material of the neural stem cell not only initiates the transformation into a nerve cell, it also blocks this process again immediately. Or, as Utz Fischer explains: “The gene that is responsible for repressing differentiation in neural stem cells codes for both the mRNA that is required for it and, simultaneously, a microRNA from the miR-26 family.” And it is this microRNA that blocks the mRNA formed in parallel with it.

    “At first glance, this makes absolutely no sense. But we do know that cells do not normally fool around,” says Utz Fischer. The scientists therefore began to search for other factors that may regulate this blockade. They found what they were looking for in a mechanism that suppresses the creation of active miR-26 microRNA until it is needed by the cell.

    Why does a stem cell actually have to be prevented from transforming into a nerve cell? That is, after all, its actual goal. “Because then you would only have a few nerve cells rather than the umpteen billion you need,” says Linder. Stem cells have to divide and multiply before they differentiate. But they can only do this for as long as the transformation process is blocked.

    Promising approach for cancer treatment

    The fact that miR-26 microRNA stimulates cells to differentiate and in so doing stops the division process is also interesting from a medical point of view, providing a potential avenue for cancer treatment, for example. After all, uncontrolled cell division is the main attribute of cancer. In fact, another research group from The Johns Hopkins University in Baltimore has recently achieved a promising breakthrough in this area: it has managed to stop tumors growing in mice with a particular form of liver cancer by administering miR-26 microRNA.

    However, this is not the direction that Fischer and his team are heading in with their research. They see their work rather as basic research: “Our focus is on understanding the network of regulation in a cell and the underlying mechanisms,” says Linder. And this has been achieved perfectly with the recent publication: “It has long been predicted that control loops must exist where genes virtually repress themselves. We have now been able to prove this in a living organism.”

    But the search is far from over. “There must be other factors that regulate the formation of active microRNA,” says Linder. Knowing these would be “a major step forward”.

    “Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2”, Holger Dill, Bastian Linder, Alexander Fehr, and Utz Fischer. Genes & Development; doi:10.1101/gad.177774.111

    “The enemy within: intronic miR-26b represses its host gene, ctdsp2, to regulate neurogenesis”, Jinju Han, Ahmet M. Denli, and Fred H. Cage. Genes & Development; doi:10.1101/gad.184416.111


    Prof. Dr. Utz Fischer, T: +49 (0)931 31-84029, e-mail: utz.fischer@biozentrum.uni-wuerzburg.de

    By Gunnar Bartsch