Ets transcription factor Pointed promotes the generation of intermediate neural progenitors in Drosophila larval brains

Department of Physiology, University of California, San Francisco, CA 94158, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2011; 108(51):20615-20. DOI: 10.1073/pnas.1118595109
Source: PubMed


Intermediate neural progenitor (INP) cells are transient amplifying neurogenic precursor cells generated from neural stem cells. Amplification of INPs significantly increases the number of neurons and glia produced from neural stem cells. In Drosophila larval brains, INPs are produced from type II neuroblasts (NBs, Drosophila neural stem cells), which lack the proneural protein Asense (Ase) but not from Ase-expressing type I NBs. To date, little is known about how Ase is suppressed in type II NBs and how the generation of INPs is controlled. Here we show that one isoform of the Ets transcription factor Pointed (Pnt), PntP1, is specifically expressed in type II NBs, immature INPs, and newly mature INPs in type II NB lineages. Partial loss of PntP1 in genetic mosaic clones or ectopic expression of the Pnt antagonist Yan, an Ets family transcriptional repressor, results in a reduction or elimination of INPs and ectopic expression of Ase in type II NBs. Conversely, ectopic expression of PntP1 in type I NBs suppresses Ase expression the NB and induces ectopic INP-like cells in a process that depends on the activity of the tumor suppressor Brain tumor. Our findings suggest that PntP1 is both necessary and sufficient for the suppression of Ase in type II NBs and the generation of INPs in Drosophila larval brains.

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    • "Hyperactivity of Dpn in type II neuroblasts mimics the Notch pathway overexpression phenotype with accompanying overgrowth of neuroblast-like cells and tumour formation [103]. However, loss of dpn activity does not recapitulate the neuronal hypoplasia seen in Notch pathway mutants [74,103]. This conundrum seems to indicate that Dpn may act redundantly with other proteins to regulate type II neuroblast homoeostasis. "
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    ABSTRACT: Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumor-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate asymmetric cell division (ACD). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumor formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in asymmetric cell division in mammalian systems may play significant roles in the series of pathogenic events leading to the development of brain cancers.
    Full-text · Article · Jun 2014 · Bioscience Reports
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    • "This is not due to apoptosis because the phenotype cannot be rescued by the apoptosis inhibitor p35 (zero type II NBs detected, n = 7 brains) (Figure S6M). Twenty-four hours after the induction of Ham expression by PntP1-GAL4 (McGuire et al., 2004; Zhu et al., 2011), the average NB diameter decreased by 22% (control 11.5 ± 0.5 mm SEM [n = 10 type II NBs], and UAS-ham 8.9 ± 0.2 mm SEM [n = 10 type II NBs]; p < 0.001). In addition, 64% of type II NBs activated Ase (n = 14 type II NBs), and NBs started to downregulate the PntP1-GAL4 driver (Figure 6A), indicating loss of NB identity. "
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    ABSTRACT: Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP:
    Full-text · Article · Mar 2014 · Cell
    • "In contrast to the regular type I NBs that divide asymmetrically to generate a series of GMCs that each divides once to produce two postmitotic cells , type II NBs divide asymmetrically to self - renew and to generate a series of transit amplifying GMCs called intermediate neural progenitors ( INPs ) , with each INP dividing asymmetrically to generate several GMCs and eventually giving rise to 6 – 12 neurons and / or glia ( Bayraktar , Boone , Drummond , & Doe , 2010 ; Boone & Doe , 2008 ; Viktorin , Riebli , Popkova , Giangrande , & Reichert , 2011 ; Weng , Golden , & Lee , 2010 ; Zhu , Barshow , Wildonger , Jan , & Jan , 2011 ) . Type II lineages allow more neurons than type I lineages to be quickly generated . "
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    ABSTRACT: Drosophila has recently become a powerful model system to understand the mechanisms of temporal patterning of neural progenitors called neuroblasts (NBs). Two different temporal sequences of transcription factors (TFs) have been found to be sequentially expressed in NBs of two different systems: the Hunchback, Krüppel, Pdm1/Pdm2, Castor, and Grainyhead sequence in the Drosophila ventral nerve cord; and the Homothorax, Klumpfuss, Eyeless, Sloppy-paired, Dichaete, and Tailless sequence that patterns medulla NBs. In addition, the intermediate neural progenitors of type II NB lineages are patterned by a different sequence: Dichaete, Grainyhead, and Eyeless. These three examples suggest that temporal patterning of neural precursors by sequences of TFs is a common theme to generate neural diversity. Cross-regulations, including negative feedback regulation and positive feedforward regulation among the temporal factors, can facilitate the progression of the sequence. However, there are many remaining questions to understand the mechanism of temporal transitions. The temporal sequence progression is intimately linked to the progressive restriction of NB competence, and eventually determines the end of neurogenesis. Temporal identity has to be integrated with spatial identity information, as well as with the Notch-dependent binary fate choices, in order to generate specific neuron fates.
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