Newswise — The central question of developmental biology is how a single fertilized egg can divide repeatedly to produce multiple different cell types. An article in this week's issue of the journal Cell from Jürgen Knoblich's group at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna sheds fresh light on this key issue " and is likely to be highly relevant to the development of cancer in humans.
It had previously been established that asymmetric cell division is extremely important in determining cell fates. Asymmetric cell division occurs when a molecule is inherited by only one of the two cells that arise following cell division (mitosis). The process can be compared to a children's puzzle in which a sphere containing a number of differently coloured balls on either side of a divide is shaken until all the balls of one colour are together on one side, with all the balls of the other colour on the other side. With a little patience most schoolchildren can manage this. But cells have a much more difficult task: they must ensure that all the "balls" (in reality proteins that control or affect various intracellular processes) are segregated at the appropriate time, so that the cells divide to produce offspring that differ substantially from each other. Only in this way can a single cell divide repeatedly to give rise to the complicated organism that is man " or the fruit fly Drosophila melanogaster.
The principle of asymmetric cell division may be simple but how it occurs has been taxing the minds of biologists for generations. About fifteen years ago there was a major advance, when a system to investigate the process was discovered. In particular cells (sensory organ precursor cells or SOP cells) of the fly the so-called "Numb" protein is segregated into only one of the two daughter cells that result from cell division.
This groundbreaking discovery was made in the lab of Lily and Yuh Nung Jan at the University of California at San Francisco (UCSF) and Knoblich was one of the scientists involved. When he left UCSF he was determined to understand the underlying mechanism and he took up a position at the Research Institute of Molecular Pathology (IMP) in Vienna with this goal clearly in mind.
The infrastructure at the IMP and its partner-institute IMBA, to which Knoblich moved in 2004, enabled a wide range of methods to be brought to bear on the problem. Knoblich has been studying Numb localization by means of a uniquely multidisciplinary approach, combining genetics and biochemistry with a recently developed method for visualizing live flies. He is enthusiastic about the facilities at the two institutes in Vienna. "There's a whole range of techniques set up here and all of them are freely available to everyone. The live imaging method was especially important - without it our experiments would simply not have been possible."
Some time ago, Knoblich and others showed that the protein "Lethal giant larvae" (Lgl) was involved, as were two protein kinases, named aPKC and Aurora-A (AurA). Protein kinases are proteins that chemically modify (phosphorylate) other proteins and are known to have key roles in the control and coordination of a large number of cellular processes. aPKC was known to phosphorylate Lgl, while Aur-A was known to be switched on at the start of cell division and to be required for Numb activity, which gave a clue that it might be involved in Numb's asymmetric segregation.
Knoblich has now shown that AurA phosphorylates a further protein known as Par-6, which causes activation of the kinase aPKC and thus phosphorylation of Lgl. When Lgl is phosphorylated it no longer binds to a multiprotein complex known as "Par" and Par is free to bind a further protein, fascinatingly termed "Bazooka" . In other words, when AurA is activated, the entire Par complex is remodelled.
Knoblich went on to prove that, unlike the initial, Lgl-bound form, the remodelled Par complex is able to phosphorylate the Numb protein. When Numb is phosphorylated it no longer binds to the complex but is released and because it only moves slowly through the cell cortex it is localized in a very precise way.
Taken together, Knoblich's results have identified a chain of interactions among the various proteins required for restricting Numb's localization. The activation of the AurA kinase at the start of cell division leads inexorably to the segregation of Numb to only one of the two daughter cells that result from mitosis. Our shoolchildren now only have to press a button to cause all the balls of one colour to go automatically to one side of the divide in the cell.
These results on the fruit fly are likely to turn out to have important ramifications in human medicine. Many of the components involved in asymmetric cell division in fly cells have homologues (counterparts) in humans and the segregation of molecules during mitosis in cultured human cells seems to be controlled in a highly similar manner. The molecular mechanism responsible for regulating asymmetric cell division in Drosophila may thus control self-renewal and prevent tumour formation in other types of stem cell.
Mutations in the fly numb gene have been shown to lead to the formation of brain tumours, and a permanently active form of aPKC has a similar effect. The human Numb homologue is known to act as a suppressor of breast cancer, whereas the Lgl homologue has been linked to metastasis of colon carcinomas.
The potential implications of Knoblich's latest results for human therapy are thus enormous, although Knoblich stresses that they lie well in the future. As Knoblich says "The idea that we might be able to develop drugs to prevent cell division from getting out of control is extremely appealing but we all now how long it takes for drugs to come on the market even when the idea seems so good."
More information on the Knoblich lab:http://www.imba.oeaw.ac.at/research/juergen-knoblich/
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