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Alternate Endings

05.06.2013

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Drs. Keren Yacobi-Sharon and Eli Arama
          

 

 

 

 

 

 

 

 

 

 

 

 

To save lives, it is sometimes vital to know as much as possible about death, in particular, the death of cells. For example, cancer chemotherapy works by activating a cellular death program called apoptosis. But if the molecular machinery of apoptosis is defective, or if the cancer cells learn to avoid apoptosis, which indeed they often do, chemotherapy becomes ineffective. Therefore, the recent discovery at the Weizmann Institute of so-called germ cell death – an alternative cell death pathway – can be of great value for the development of future life-saving therapies.

 

In short

    Some germ cells – sperm precursors – undergo a special form of cell death that ensures quality control.
    Germ cell death differs from the main type – apoptosis – in a number of crucial ways.
•    These may point to new mechanisms for anti-cancer therapies.

In the study, which was reported in Developmental Cell, Dr. Eli Arama, senior intern Dr. Keren Yacobi-Sharon and graduate student Yuval Namdar, all of the Molecular Genetics Department, revealed a new mechanism that is responsible for the death of some male germ cells, the precursor cells that give rise to sperm, in the testis of the adult fruit fly.

Sperm cells are formed in a seemingly wasteful manner, which probably serves to ensure quality control: Germ cells are constantly created in large numbers, after which many of them die. By tracking the death of those cells in a living organism, the researchers were able to reveal its mechanics in great detail.
 
 
In an adult fruit fly testis, viewed under a confocal microscope, maturing germ cells (a nonapoptotic process) use active caspases (green); in contrast, dying germ cells (red) do not express activated caspases
 
First of all, the scientists confirmed that these germ cells do not die by apoptosis, the most common type of cell death. In particular, they showed that effector caspases, the destructive enzymes that execute apoptotic death, are not involved in germ cell death. Next, they defined the structural hallmarks of germ cell death. Like in apoptosis, the entire cell and its nucleus shrink, and the DNA becomes fragmented. However, many typical apoptotic features are missing in dying germ cells; moreover, unlike in apoptosis, these cells contain large degrading regions and their mitochondria, the energy-producing organelles, become distorted.  

The researchers discovered that a central role in germ cell death is played by the mitochondria: These organelles activate a particular gene, htrA2, which makes a destructive protease enzyme. HtrA2 has an equivalent in organisms ranging from bacteria to mammals, which suggests that the findings of the Weizmann fruit fly study are applicable to humans. Yet another major component of the germ cell death mechanism is the lysosome, the cell’s stomach-like organelle that is filled with enzymes for breaking down cellular waste and debris. Lysosomes contribute to cellular destruction by spilling out their contents.
 
Why do the cells need an alternative death pathway? One possible explanation is that germ cell death is the more ancient in evolutionary terms, while apoptosis, as well as the involvement of caspases in apoptotic death, may have evolved more recently. That could be why flowers and yeast lack conventional caspases and make use of a cell death pathway that is similar to germ cell death, whereas cell death is not the only function of the caspases in multicellular animals.
The tips of two adult fruit fly testes, viewed under a confocal microscope, are filled with dividing germ cells (green). About one quarter of these germ cells die by an alternative death pathway called germ cell death (pink and red)
 
Knowing the mechanism of germ cell death might have important implications for cancer research, among other things. It may, for instance, help explain the origins of testicular cancer, in which germ cells in the testes multiply uncontrollably. On a more general level, it may help in the development of anti-cancer drugs that could kill cells by an entirely new mechanism, helping to overcome the drug resistance that often emerges in response to more conventional chemotherapy.
 
Dr. Eli Arama’s research is supported by the Yeda-Sela Center for Basic Research; the Fritz Thyssen Stiftung; and the late Rudolfine Steindling. Dr. Arama is the incumbent of the Corinne S. Koshland Career Development Chair in Perpetuity.
 

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