Molecular Biology Research

Lethal Legacies

Understanding cell death on a molecular level

30.12.2015 | Programmed cell death, also known as apoptosis, is universal in higher organisms. Now a research team headed by Barbara Conradt, Professor of Cell and Developmental Biology in Munich, have uncovered a mechanism that induces apoptosis in the nematode C. elegans: in this case, the mother cell actively determines the fate of the daughter cell.
Apoptosis is a tightly regulated process that results in the disposal of damaged or unwanted cells. The latter variant is particularly important in the course of embryonic development, during which many more cells are produced than are ultimately required. During the embryonic development of C. elegans, precisely 1090 cells are generated by cell division, of which 131 undergo programmed cell death. Since the entire schedule of cell division and cell death is known for this organism, it has become a favorite system for the investigation of apoptosis. And because essentially the same process is observed in all higher organisms, the insights gained from C. elegans can be applied to other animals, including humans.

Prof. Barbara Conradt
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Prof. Barbara Conradt
Apoptosis involves a precisely defined series of steps. The first step determines which cells are to be eliminated, and the second carries out the sentence by forcing the cells to commit suicide. "When a cell is dying, it goes through a characteristic series of morphological alterations and, in the end, it is engulfed and digested by neighboring cells," Prof. Conradt explains. "It has been known for the past 15 years or so that the cellular pathways that initiate and mediate engulfment are involved not only in the disposal of the dead cell, but also play a role in the actual killing. We have now discovered how they do this."

The researchers focused on a particular cell lineage in the C. elegans embryo, the so-called NSM lineage. The NSM mother cell divides asymmetrically, resulting in two daughter cells of unequal size, with the smaller one surviving for a very short time. "Up until now, it was believed that the apoptotic machinery is activated only in the smaller daughter cell after the division of the mother cell," Conradt explains. "But we found that it is already activated – at least to a certain degree - in the mother cell. Moreover, in this pre-activated state, the apoptotic machinery produces a signal that activates the engulfment pathways in specific neighboring cells. And these adjacent cells then help the mother cell to polarize and to concentrate the cell-death protein CED-3 (...). Thus, the mother cell determines the cell death fate of the smaller daughter by asymmetric segregation of CED-3."

CED-3 is known to function as a killer factor, which activates the apoptotic program. "So, prior to cell division, the mother cell is already actively engaged in 'assisting' the smaller daughter cell to kill itself, by supplying it with an overdose of cell-death-promoting factors," Conradt concludes. She and her colleagues now plan to analyze this process further and to ask whether it also takes place in mammalian tissues or stem cells. "Unequal segregation of resources may be especially important in stem cells, which also divide asymmetrically, as factors that may be deleterious to the surviving cell can be disposed of by loading them into the daughter cell that is fated to die," says Conradt.

The research group of Prof. Conradt focuses on the molecular biology of apoptosis, because it plays a crucial role in health maintenance, as errors in the process can be harmful for the whole organism. Many disorders have been linked to errors in the control of apoptosis, like certain cancers, neurodegenerative disorders and autoimmune diseases. Thus a better understanding of the mechanisms underlying apoptosis could in the future help to identify targets for the development of new therapeutics.
  (© Ludwig Maximilians University of Munich LMU, AcademiaNet)

More information

Source

  • Sayantan Chakraborty, Eric J. Lambie, Samik Bindu, Tamara Mikeladze-Dvali, Barbara Conradt: Engulfment pathways promote programmed cell death by enhancing the unequal segregation of apoptotic potential, Nature Communications 2015, published December 10, 2015, DOI: 10.1038/ncomms10126

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