Article

Linking Cell Cycle to Asymmetric Division: Aurora-A Phosphorylates the Par Complex to Regulate Numb Localization

Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
Cell (Impact Factor: 33.12). 11/2008; 135(1):161-73. DOI: 10.1016/j.cell.2008.07.049
Source: PubMed

ABSTRACT Drosophila neural precursor cells divide asymmetrically by segregating the Numb protein into one of the two daughter cells. Numb is uniformly cortical in interphase but assumes a polarized localization in mitosis. Here, we show that a phosphorylation cascade triggered by the activation of Aurora-A is responsible for the asymmetric localization of Numb in mitosis. Aurora-A phosphorylates Par-6, a regulatory subunit of atypical protein kinase C (aPKC). This activates aPKC, which initially phosphorylates Lethal (2) giant larvae (Lgl), a cytoskeletal protein that binds and inhibits aPKC during interphase. Phosphorylated Lgl is released from aPKC and thereby allows the PDZ domain protein Bazooka to enter the complex. This changes substrate specificity and allows aPKC to phosphorylate Numb and release the protein from one side of the cell cortex. Our data reveal a molecular mechanism for the asymmetric localization of Numb and show how cell polarity can be coupled to cell-cycle progression.

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    • "In Drosophila, SOP stem cells provide a well-studied biological example model of asymmetric stem cell division, see e.g. [25] [23] [24] and the references therein. "
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    ABSTRACT: During asymmetric stem cell division so-called cell-fate determinants are localised and become inherited into only one of the two daughter cells. In Drosophila SOP precursor cells, this biological mechanism is centred around the phosphorylation of a key protein call Lgl (Lethal giant larvae). In this paper, we present a surface-volume reaction diffusion system, which models the localisation of Lgl within the cell cytoplasm and on the cell cortex. We prove well-posedness of global solutions as well as regularity of the solutions. Moreover, we rigorously perform a fast reaction limit to a reduced quasi-steady-state approximation system, when phosphorylated Lgl is instantaneously expelled from the cortex.
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    • "Overexpression of Lgl partially rescues the slmb polarity phenotype Lgl might play a redundant role in the polarisation of the oocyte, since it localises to the posterior cortex and is a known antagonist of aPKC (Tian and Deng, 2008; Wirtz-Peitz et al., 2008). We examined the effects of overexpressing UAS-Lgl-GFP in slmb mutants. "
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    ABSTRACT: The Drosophila anterior-posterior axis is specified when the posterior follicle cells signal to polarise the oocyte, leading to the anterior/lateral localisation of the Par-6/aPKC complex and the posterior recruitment of Par-1, which induces a microtubule reorganisation that localises bicoid and oskar mRNAs. Here we show that oocyte polarity requires Slmb, the substrate specificity subunit of the SCF E3 ubiquitin ligase that targets proteins for degradation. The Par-6/aPKC complex is ectopically localised to the posterior of slmb mutant oocytes, and Par-1 and oskar mRNA are mislocalised. Slmb appears to play a related role in epithelial follicle cells, as large slmb mutant clones disrupt epithelial organisation, whereas small clones show an expansion of the apical domain, with increased accumulation of apical polarity factors at the apical cortex. The levels of aPKC and Par-6 are significantly increased in slmb mutants, whereas Baz is slightly reduced. Thus, Slmb may induce the polarisation of the anterior-posterior axis of the oocyte by targeting the Par-6/aPKC complex for degradation at the oocyte posterior. Consistent with this, overexpression of the aPKC antagonist Lgl strongly rescues the polarity defects of slmb mutant germline clones. The role of Slmb in oocyte polarity raises an intriguing parallel with C. elegans axis formation, in which PAR-2 excludes the anterior PAR complex from the posterior cortex to induce polarity, but its function can be substituted by overexpressing Lgl.
    Development 08/2014; 141(15):2984-92. DOI:10.1242/dev.109827 · 6.27 Impact Factor
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    • "The VZ plays a central role in a complex and sequential process, requiring precise control of cell cycle progression, fate commitment, differentiation, and migration. Symmetric or asymmetric localization of subcellular components (Morin and Bellaïche, 2011), the Par complex (Wirtz-Peitz et al., 2008), signaling pathways including Notch (De la Pompa et al., 1997; Caviness et al., 2009), and the intercellular FGF and Wnt signaling pathways all interact with each other to regulate both proliferation and differentiation in the VZ of the neocortex (Johansson et al., 2010). "
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    ABSTRACT: Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis. We used a mouse in situ hybridization dataset (The Allen Institute for Brain Science) to identify 13 genes (Cdon, Celsr1, Dbi, E2f5, Eomes, Hmgn2, Neurog2, Notch1, Pcnt, Sox3, Ssrp1, Tead2, Tgif2) with high correlation of expression in the proliferating cells of the VZ of the neocortex at early stages of development (E15.5). We generated a similar human brain network using microarray and RNA-seq data (BrainSpan Atlas) and identified 407 genes with high expression in the developing human VZ and subventricular zone (SVZ) at 8-9 post-conception weeks. Seven of the human genes were also present in the mouse VZ network. The human and mouse networks were extended using available genetic and proteomic datasets through GeneMANIA. A gene ontology search of the mouse and human networks indicated that many of the genes are involved in the cell cycle, DNA replication, mitosis and transcriptional regulation. The reported involvement of Cdon, Celsr1, Dbi, Eomes, Neurog2, Notch1, Pcnt, Sox3, Tead2 and Tgif2 in neural development or diseases resulting from the disruption of neurogenesis validates these candidate genes. Taken together, our knowledge-based discovery method has validated the involvement of many genes already known to be involved in neocortical development and extended the potential number of genes by 100's, many of which are involved in functions related to cell proliferation but others of which are potential candidates for involvement in the regulation of neocortical development.
    Frontiers in Neuroscience 08/2014; 8. DOI:10.3389/fnins.2014.00257 · 3.70 Impact Factor
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