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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    • "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.
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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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    • "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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