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Prof. Michal Neeman and team. Ferrritin reporter gene
Reporters broadcast news about current events, trends and people "live" from the scene. Today's viewers need only tune in to this news, wherever and whenever it is taking place, to find out what's going on in the world.
Molecular biologists are faced with the much more difficult task of trying to keep abreast of events occurring within the world of an organism. In humans, for example, scientists need to keep tabs on the activities of the estimated 20,000 – 30,000 genes that code for proteins. To complicate things further, these thousands of genes can be expressed (i.e., converted into functional proteins) in many different combinations.
Gene expression, in turn, controls many events in the body: the structure and function of a cell, various processes such as blood flow and even the progression of certain diseases such as cancer.
Scientists need ways of getting an up-close look at events in which genes are controlled by the different regulatory mechanisms. To make their job easier, they employ reporter genes – genes that code for an easily detectable protein. The popular green fluorescent protein (GFP) reporter gene, for example, is widely used by scientists for this purpose. This gene "broadcasts" its reports by giving off light when it is expressed. Researchers insert the reporter DNA into a specific region of a gene they want to study, and it flashes its message back, filling them in on how this gene is regulated, where the regulation occurs and what the activity leads to in the end. But not all reporter genes are ideal for every situation. In particular, it is difficult to detect the location and intensity of fluorescent proteins in animals or people, especially when expression of the intended gene is localized deep within the body.
Alternatives have been suggested. In particular, considerable effort has been invested in developing reporter genes whose signals can be detected by magnetic resonance imaging (MRI), a non-invasive technique that is already widely used on humans and animals. Unfortunately, most of the candidate reporters proposed so far require the administration of additional substances, called reporter probes, before the MRI can detect their signals. Such substances are shut out of many cellular events – such as fetal development or those events taking place within the central nervous system, as both present barriers that the reporter probes can't cross.
In searching for a new reporter gene that would circumvent this problem, Weizmann Institute scientists have come across a promising candidate: ferritin. According to its resume, ferritin works by chemically neutralizing iron. This protein normally minimizes iron toxicity in the cell, but when it's overexpressed, it also causes signal changes in the surrounding environment that are strong enough to be detected by MRI; no additional substrate is needed.
Prof. Michal Neeman and Dr. Batya Cohen of the Biological Regulation Department, along with research students Keren Ziv and Vicki Plaks and their colleagues, decided to give ferritin a chance to show its stuff. The scientists sent it "on assignment" by inserting the ferritin gene into a circular piece of DNA, which was in turn introduced into a special mouse strain they had developed that allows the introduced ferritin gene to be expressed in a controlled manner. They also sent along the old hand – the GFP reporter gene – which they inserted next to the ferritin gene to check independently whether it was reporting events accurately. In a further test of the method, the scientists introduced an additional gene, one that acts like a switch – it can turn both reporters either "on" or "off" simultaneously – to make sure that the signals detected actually come from the reporters themselves, and not from another source.
So far, their results, which were published in the journal Nature Medicine, show that ferritin can function as a reporter, broadcasting its reports live, via MRI detection, from the liver, endothelial cells and even during fetal development in the pregnant mouse, all without help from other materials.
Cohen: "These new results have shown that the use of ferritin as a reporter of gene expression and biological activity, especially in live animals, is not only feasible but more efficient than that of other MRI reporter genes tested so far. This approach could open many additional possibilities for studying the activation of genes during different stages of development, or detailed studies of various disease models in strains of mice bred for this purpose."
This method grew out of a joint vision that originated 10 years ago in collaboration with the late Dr. Yoav Citri.


Overexpressed ferritin shows up in MRI


Ferritin-induced contrast