Guo, M., Jan, L. Y. & Jan, Y. N. Control of daugher cell fates during asymmetric division; interaction of Numb and Notch. Neuron 17, 27-41

Howard Hughes Medical Institute, University of California, San Francisco 94143-0724, USA.
Neuron (Impact Factor: 15.05). 08/1996; 17(1):27-41. DOI: 10.1016/S0896-6273(00)80278-0
Source: PubMed


During development of the Drosophila peripheral nervous system, a sensory organ precursor (SOP) cell undergoes rounds of asymmetric divisions to generate four distinct cells of a sensory organ. Numb, a membrane-associated protein, is asymmetrically segregated into one daughter cell during SOP division and acts as an inherited determinant of cell fate. Here, we show that Notch, a transmembrane receptor mediated cell-cell communication, functions as a binary switch in cell fate specification during asymmetric divisions of the SOP and its daughter cells in embryogenesis. Moreover, numb negatively regulates Notch, probably through direct protein-protein interaction that requires the phosphotyrosine-binding (PTB) domain of Numb and either the RAM23 region or the very C-terminal end of Notch. Notch then positively regulates a transcription factor encoded by tramtrack (ttk). This leads to Ttk expression in the daughter cell that does not inherit Numb. Thus, the inherited determinant Numb bestows a bias in the machinery for cell-cell communication to allow the specification of distinct daughter cell fates.

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    • "In agreement with this, our ChIP data identified in vivo Ttk69 binding in the vicinity of multiple genes encoding components of the Notch pathway (data not shown), indicating that Ttk69 has at least the potential to contribute to negative-feedback regulation directly. Although speculative, the many links between Notch signaling and Ttk in other contexts, including the fact that ectopic Notch signal is sufficient to induce Ttk expression in the peripheral nervous system (Guo et al., 1996), suggest that Ttk might be responsive to Notch signaling in FCMs as well. "
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    ABSTRACT: Molecular models of cell fate specification typically focus on the activation of specific lineage programs. However, the concurrent repression of unwanted transcriptional networks is also essential to stabilize certain cellular identities, as shown in a number of diverse systems and phyla. Here, we demonstrate that this dual requirement also holds true in the context of Drosophila myogenesis. By integrating genetics and genomics, we identified a new role for the pleiotropic transcriptional repressor Tramtrack69 in myoblast specification. Drosophila muscles are formed through the fusion of two discrete cell types: founder cells (FCs) and fusion-competent myoblasts (FCMs). When tramtrack69 is removed, FCMs appear to adopt an alternative muscle FC-like fate. Conversely, ectopic expression of this repressor phenocopies muscle defects seen in loss-of-function lame duck mutants, a transcription factor specific to FCMs. This occurs through Tramtrack69-mediated repression in FCMs, whereas Lame duck activates a largely distinct transcriptional program in the same cells. Lineage-specific factors are therefore not sufficient to maintain FCM identity. Instead, their identity appears more plastic, requiring the combination of instructive repressive and activating programs to stabilize cell fate.
    Journal of Cell Science 07/2014; 141(13):2633-43. DOI:10.1242/dev.101956 · 5.43 Impact Factor
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    • "However mutations affecting the inhibitors numb and Hairless (H) result in more specific phenotypes of ectopic Notch activity [e.g. [106,107]]. The numb phenotype has been exploited in the larval CNS where ectopic Notch causes the neural stem cells to over-proliferate giving rise to tumours [108–110]. "
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    ABSTRACT: Notch signaling involves a highly conserved pathway that mediates communication between neighboring cells. Activation of Notch by its ligands, results in the release of the Notch intracellular domain (NICD), which enters the nucleus and regulates transcription. This pathway has been implicated in many developmental decisions and diseases (including cancers) over the past decades. The simplicity of the Notch pathway in Drosophila melanogaster, in combination with the availability of powerful genetics, make this an attractive model for studying fundamental principles of Notch regulation and function. In this chapter we present some of the established and emerging tools that are available to monitor and manipulate the Notch pathway in Drosophila and discuss their strengths and weaknesses.
    Methods 04/2014; 68(1). DOI:10.1016/j.ymeth.2014.03.029 · 3.65 Impact Factor
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    • "We have generated a new Notch ICN construct (UAS-RICN, consistent of ICN plus the complete RAM domain) that was overexpressed in the developing thorax and head using the Bx-Gal4 driver line. As expected from the earlier reports [28,40,42,46,54], this overexpression resulted in double and quadruple sockets instead of a normally formed bristle (Figure 2B). Compared to the wild type, where ICN mediated activator complexes and Hairless mediated repressor complexes are balanced (Figure 2A), the overexpression of ICN entails a shift towards activator complexes, accompanied by cell fate changes (Figure 2B). "
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    ABSTRACT: The Notch signaling pathway is instrumental for cell fate decisions. Signals from the Notch receptor are transduced by CSL-type DNA-binding proteins. In Drosophila, this protein is named Suppressor of Hairless [Su(H)]. Together with the intracellular domain of the activated Notch receptor ICN, Su(H) assembles a transcriptional activator complex on Notch target genes. Hairless acts as the major antagonist of the Notch signaling pathway in Drosophila by means of the formation of a repressor complex together with Su(H) and several co-repressors. Su(H) is characterized by three domains, the N-terminal domain NTD, the beta-trefoil domain BTD and the C-terminal domain CTD. NTD and BTD bind to the DNA, whereas BTD and CTD bind to ICN. Hairless binds to the CTD, however, to sites different from ICN. In this work, we have addressed the question of competition and availability of Su(H) for ICN and Hairless binding in vivo. To this end, we overexpressed the CTD during fly development. We observed a strong activation of Notch signaling processes in various tissues, which may be explained by an interference of CTD with Hairless corepressor activity. Accordingly, a combined overexpression of CTD together with Hairless ameliorated the effects, unlike Su(H) which strongly enhances repression when overexpressed concomitantly with Hairless. Interestingly, in the combined overexpression CTD accumulated in the nucleus together with Hairless, whereas it is predominantly cytoplasmic on its own.
    PLoS ONE 11/2013; 8(11):e81578. DOI:10.1371/journal.pone.0081578 · 3.23 Impact Factor
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