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

ArticleinNeuron 17(1):27-41 · August 1996with13 Reads
DOI: 10.1016/S0896-6273(00)80278-0 · Source: PubMed
Abstract
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.
    • "We found that Rab11DN expression in either wildtype or numb mutant sensory organ cells significantly increased the number of sensory organs containing neurons (Fig. 5B). Surprisingly, approximately 10% of all organs in numb/Rab11DN sensory organs exhibited multiple ELAVexpressing neuronal cells, a phenotype that was not observed in either wildtype or numb mutant external sensory organs, but consistent with pIIa to pIIb cell fate transformations observed in Notch mutants (Guo et al., 1996). We conclude from this data that Rab11 activity contributes to excess Notch signaling activity in numb mutant pIIb cells. "
    [Show abstract] [Hide abstract] ABSTRACT: The Notch signaling pathway plays essential roles in both animal development and human disease. Regulation of Notch receptor levels in membrane compartments has been shown to impact signaling in a variety of contexts. Here, we used steady state and pulse labeling techniques to follow Notch receptors in sensory organ precursor cells (SOP) in Drosophila. We find that the endosomal adaptor protein Numb regulates levels of Notch receptor trafficking to Rab7-labeled late endosomes, but not early endosomes. Using an assay we developed that labels different pools of Notch receptors as they move through the endocytic system, we show that Numb specifically suppresses a recycled Notch receptor subpopulation, and that excess Notch signaling in numb mutants requires the recycling endosome GTPase Rab11 activity. Our data therefore suggest that Numb controls the balance between Notch receptor recycling and receptor targeting to late endosomes to regulate signaling output following asymmetric cell division in Drosophila neural progenitors.
    Article · Jul 2016
    • "One possible explanation for SO with multiple bristles and with supernumerary cells in pupae expressing Cdk1F would be if aberrant SO were formed from multiple SOPs. Another possibility would be that multiple bristles resulted from a cell fate transformation of presumptive pIIb cells to a pIIa cell fate, similar to numb loss-of-function or Notch gain-of-function mutants (Frise et al., 1996; Guo et al., 1996; Justice et al., 2003; Rebay et al., 1993; Uemura et al., 1989). In the former case, we would expected the transformed SO to harbor multiple neurons. "
    [Show abstract] [Hide abstract] ABSTRACT: Developmentally regulated cell cycle arrest is a fundamental feature of neurogenesis, whose significance is poorly understood. During Drosophila sensory organ (SO) development, primary progenitor (pI) cells arrest in G2-phase for precisely defined periods. Upon re-entering the cell cycle in response to developmental signals, these G2-arrested precursor cells divide and generate specialized neuronal and non-neuronal cells. To study how G2-phase arrest affects SO lineage specification, we forced pI-cells to divide prematurely. This produced SO with normal neuronal lineages but supernumerary non-neuronal cell types. The reason was that prematurely dividing pI-cells generated a secondary pI-cell that produced a complete SO and an external precursor cell that underwent amplification divisions producing supernumerary non-neural cells. This means that pI-cells are capable to undergo self-renewal before transit to a terminal mode of division. Regulation of G2-phase arrest therefore serves a dual role in SO development: preventing progenitor self-renewal and synchronizing cell division with developmental signals. Cell cycle arrest in G2-phase therefore temporally coordinates the precursor cells proliferation potential with terminal cell fate determination to ensure formation of organs with a normal set of sensory cells.
    Full-text · Article · Feb 2016
    • "Notch pathway activity is detected in NBs and contributes to their maintenance. During mitosis, one of the key determinants that is segregated asymmetrically into the GMC daughter is Numb, a potent inhibitor of Notch signalling (Babaoglan et al., 2009; Connor-giles et al., 2003; Guo et al., 1996; Le Borgne et al., 2005; Rhyu et al., 1994; Spana and Doe, 1996; Wang et al., 2006). Perturbations in Numb function lead to uncontrolled proliferation of NBs and the formation of brain tumours. "
    [Show abstract] [Hide abstract] ABSTRACT: Notch signalling is involved in a multitude of developmental decisions and its aberrant activation is linked to many diseases, including cancers. One such example is the neural stem cell tumours that arise from constitutive Notch activity in Drosophila neuroblasts. To investigate how hyper-activation of Notch in larval neuroblasts leads to tumours, we combined results from profiling the upregulated mRNAs and mapping the regions bound by Su(H) (the core Notch pathway transcription factor). This identified 246 putative direct Notch targets. These genes were highly enriched for transcription factors (TFs) and overlapped significantly with a previously identified regulatory programme dependent on the proneural transcription factor Asense. Included were genes associated with the neuroblast maintenance and self-renewal programme that we validated as Notch regulated in vivo. Another group were the so-called temporal transcription factors, which have been implicated in neuroblast maturation. Normally expressed in specific time windows, several temporal transcription factors were ectopically expressed in the stem cell tumours, suggesting that Notch had reprogrammed their normal temporal regulation. Indeed, the Notch-induced hyperplasia was reduced by mutations affecting two of the temporal factors, which, conversely, were sufficient to induce mild hyperplasia on their own. Altogether the results suggest that Notch induces neuroblast tumours by promoting directly the expression of genes that contribute to stem cell identity and by re-programming the expression of factors that could regulate maturity.
    Full-text · Article · Dec 2015
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