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Solving the puzzle of stem cell division

06.10.2008
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 scientific journal Cell from Jürgen Knoblich's group at the Institute of Molecular Biotechnology (IMBA) in Vienna, Austria sheds fresh light on this key issue.

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).

It was established well over a decade ago that in the sensory organ precursor cells (SOP cells) of the fruit fly Drosophila melanogaster the "Numb" protein is segregated into only one of the two daughter cells. How this takes place, however, has remained a matter of conjecture despite the intense efforts of at least 10 groups worldwide.

Knoblich was one of the scientists involved in the early characterization of the molecules involved in Numb's asymmetric localization and he has continued to study the mechanism from his early post-doc days to the present. Some time ago he and others showed that the protein "Lethal giant larvae" (Lgl) and an atypical protein kinase C (aPKC) were involved but scientists were unable to say how the phosphorylation of Lgl by aPKC affected Numb's localization.

The facilities at the IMBA and the adjoining Institute for Molecular Pathology (IMP) have enabled a wide range of methods to be brought to bear on the problem. Key to Knoblich's work has been a recently developed method for imaging live flies. Knoblich has been studying Numb localization by means of a uniquely multidisciplinary approach, combining live imaging methods with genetics and biochemistry. The kinase AuroraA (Aur-A) was known to be activated at the start of cell division and to be required for Numb activity. Knoblich has now shown that AurA phosphorylates a protein known as Par-6, causing actication of aPKC and thus the phosphoylation of Lgl and its dissociation from the Par complex. When Lgl is no longer bound to the Par complex, a further protein, known as "Bazooka", may bind in its place. AurA activation thus effects a remodelling of the Par complex. As Knoblich further showed, the Par complex can only phosphorylate the Numb protein when Bazooka is present in the complex. Phosphorylated Numb is released from the cortex and because it diffuses only slowly through the cell it is restricted to a crescent on the opposite side.

Knoblich's results have identified a cascade of interactions among the various proteins required for restricting Numb's localization to a cortical crescent on the opposite side of the cell. A similar process was shown to operate in cultured human cells, so it is likely that the molecular mechanism responsible for regulating asymmetric cell division in Drosophila neuroblasts may control self-renewal and prevent tumour formation in other types of stem cell. The present findings are thus likely to have important ramifications in tumour biology. Indeed, mutations in the numb gene have been shown to cause uncontrolled growth of neuroblasts, leading to the formation of brain tumours and a similar phenotype results from expression of a constitutively active form of a PKC. Knoblich now reports that in this latter case the tumourigenic activity is completely removed by overexpressing Numb. The human Numb analogue is known to act as a suppressor of breast cancer, whereas the Lgl homologue has been implicated in metastasis of colon carcinomas (tumours are more aggressive in the absence of Lgl). The potential implications of Knoblich's latest results for human therapy are obvious, although Knoblich stresses that they lie well in the future.

Publication: Frederik Wirtz-Peitz, Takashi Nishimura, and Juergen A. Knoblich: Linking Cell Cycle to Asymmetric Division: Aurora A Phosphorylates the Par Complex to Regulate Numb Localization. Cell, October 3, 2008

F.W.P. was supported by a Ph.D. fellowship of the Boehringer Ingelheim Fonds; T.N. is supported by a long-term fellowship of the HFSP; work in J.A.K.'s lab is supported by the Austrian Academy of Sciences, FWF, WWTF, EU EUROSYSTEMS, and ONCASYM.

Contact:
Dr. Heidemarie Hurtl, IMBA Communications
Tel. +43 1 79730-3625
Mobile: +43 (0)664 8247910
heidemarie.hurtl@imba.oeaw.ac.at
Scientific Contact:
Dr. Jürgen Knoblich
juergen.knoblich@imba.oeaw.ac.at

Dr. Heidemarie Hurtl | idw
Further information:
http://www.imba.oeaw.ac.at/research/juergen-knoblich/

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