Temporal Transcription Factors and Their Targets Schedule the End of Neural Proliferation in Drosophila

MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Cell (Impact Factor: 32.24). 06/2008; 133(5):891-902. DOI: 10.1016/j.cell.2008.03.034
Source: PubMed


The timing mechanisms responsible for terminating cell proliferation toward the end of development remain unclear. In the Drosophila CNS, individual progenitors called neuroblasts are known to express a series of transcription factors endowing daughter neurons with different temporal identities. Here we show that Castor and Seven-Up, members of this temporal series, regulate key events in many different neuroblast lineages during late neurogenesis. First, they schedule a switch in the cell size and identity of neurons involving the targets Chinmo and Broad Complex. Second, they regulate the time at which neuroblasts undergo Prospero-dependent cell-cycle exit or Reaper/Hid/Grim-dependent apoptosis. Both types of progenitor termination require the combined action of a late phase of the temporal series and indirect feedforward via Castor targets such as Grainyhead and Dichaete. These studies identify the timing mechanism ending CNS proliferation and reveal how aging progenitors transduce bursts of transcription factors into long-lasting changes in cell proliferation and cell identity.

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Available from: Alex P Gould, Oct 09, 2015
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    • "Mechanistically, regulation of temporal identity in neural progenitors is best understood in invertebrate systems. In Drosophila neuroblast lineages, several transcription factor cascades have been shown to alter temporal identity over developmental time (Baumgardt et al., 2009; Bayraktar and Doe, 2013; Li et al., 2013a, 2013b; Maurange et al., 2008; Pearson and Doe, 2003). Among the best characterized of these cascades operates during motoneuron production, in which sequential expression of the transcription factors hunchback (hb), Kru¨ppel (Kr), pdm1/2, and castor (cas) is necessary and sufficient to specify fates at a given neuroblast division and/or to regulate the progression of the cascade (Cleary and Doe, 2006; Grosskortenhaus et al., 2006; Isshiki et al., 2001; Kambadur et al., 1998; Pearson and Doe, 2003). "
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    ABSTRACT: Neural progenitors alter their output over time to generate different types of neurons and glia in specific chronological sequences, but this process remains poorly understood in vertebrates. Here we show that Casz1, the vertebrate ortholog of the Drosophila temporal identity factor castor, controls the production of mid-/late-born neurons in the murine retina. Casz1 is expressed from mid/late stages in retinal progenitor cells (RPCs), and conditional deletion of Casz1 increases production of early-born retinal neurons at the expense of later-born fates, whereas precocious misexpression of Casz1 has the opposite effect. In both cases, cell proliferation is unaffected, indicating that Casz1 does not control the timing of cell birth but instead biases RPC output directly. Just as Drosophila castor lies downstream of the early temporal identity factor hunchback, we find that the hunchback ortholog Ikzf1 represses Casz1. These results uncover a conserved strategy regulating temporal identity transitions from flies to mammals. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 02/2015; 85(3). DOI:10.1016/j.neuron.2014.12.052 · 15.05 Impact Factor
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    • "In wild type, thoracic pNBs undergo self-renewal until about 120 h ALH before they differentiate terminally into neurons (Maurange et al., 2008). This final differentiation step is characterized by a lengthening of the pNB cell cycle, loss of MIRA expression and a reduction of cell size (Maurange et al., 2008). As reported above, the proliferation rate of the ball 2 mutant NBs was reduced, implying a lengthening of the cell cycle, and MIRA expression was lost from about half of NBs. "
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    ABSTRACT: Stem cells continuously generate differentiating daughter cells and are essential for tissue homeostasis and development. Their capacity to self-renew as undifferentiated and actively dividing cells is controlled by either external signals from a cellular environment, the stem cell niche, or asymmetric distribution of cell fate determinants during cell division. Here we report that the protein kinase Bällchen (BALL) is required to prevent differentiation as well as to maintain normal proliferation of neuronal stem cells of Drosophila melanogaster, called neuroblasts. Our results show that the brains of ball mutant larvae are severely reduced in size, which is caused by a reduced proliferation rate of the neuroblasts. Moreover, ball mutant neuroblasts gradually lose the expression of the neuroblast determinants Miranda and aPKC, suggesting their premature differentiation. Our results indicate that BALL represents a novel cell intrinsic factor with a dual function regulating the proliferative capacity and the differentiation status of neuronal stem cells during development.
    Biology Open 09/2014; DOI:10.1242/bio.20148631 · 2.42 Impact Factor
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    • "This includes known tumor suppressor genes and NB temporal transcription factors. Their knock down results in adult NB proliferation (Bello et al., 2006; Maurange et al., 2008) nicely confirming our screening strategy. Analysis of protein-protein and genetic interactions between the identified genes revealed three distinct interaction clusters (Figure 3D). "
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    ABSTRACT: Stem cells are highly abundant during early development but become a rare population in most adult organs. The molecular mechanisms causing stem cells to exit proliferation at a specific time are not well understood. Here, we show that changes in energy metabolism induced by the steroid hormone ecdysone and the Mediator initiate an irreversible cascade of events leading to cell-cycle exit in Drosophila neural stem cells. We show that the timely induction of oxidative phosphorylation and the mitochondrial respiratory chain are required in neuroblasts to uncouple the cell cycle from cell growth. This results in a progressive reduction in neuroblast cell size and ultimately in terminal differentiation. Brain tumor mutant neuroblasts fail to undergo this shrinkage process and continue to proliferate until adulthood. Our findings show that cell size control can be modified by systemic hormonal signaling and reveal a unique connection between metabolism and proliferation in stem cells.
    Cell 08/2014; 158:874-888. DOI:10.1016/j.cell.2014.06.024 · 32.24 Impact Factor
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