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.


Available from: Alex P Gould
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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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    • "Upon close examination of nerfin-1 159 type I tumor clones, we found that unlike wild-type NBs, which maintain a constant size of ;9–12 mm in diameter throughout neurogenesis (Maurange et al. 2008), nerfin-1 159 Mira + cells varied between 3 and 12 mm in diameter (Fig. 2I). We then correlated NB size with specific marker expression. "
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    ABSTRACT: Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc- and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of self-renewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance. © 2015 Froldi et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 01/2015; 29(2):129-43. DOI:10.1101/gad.250282.114 · 10.80 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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