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Genome wide profiling of Su(H) [CSL] binding in Drosophila melanogaster larval CNSs where Notch is hyperactive in neuroblasts for 24 hours

ABSTRACT: The Notch pathway is a well conserved cell to cell communication mechanism that is normally involved in many developmental processes and when aberrantly activated it leads to diseases such as cancer. One such example is the neural stem cell tumours that arise from constitutive Notch activity in Drosophila neuroblasts from the larval Central Nervous System (CNS). To investigate how hyper-activation of Notch in larval neuroblasts leads to tumours, we mapped genome-widely the regions that are bound by Su(H) (the core Notch pathway transcription factor, known as CSL in mammals). We combined these results with the profiling of upregulated mRNAs in CNSs where Notch is hyper-activated for 24h vs control CNSs and identified 127 putative direct Notch targets in the hyperplastic CNSs. Included were genes associated with the neuroblast maintenance and self-renewal programme and genes coding for temporal transcription factors, which are involved in neuroblast progression and generation of progeny with specific identity over time. Thus, Notch induces neural stem cell tumors by promoting the expression of genes that contribute to stem cell identity and by reprogramming expression of temporal factors that regulate maturity.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE68614 | GEO | 2015/12/15

SECONDARY ACCESSION(S): PRJNA283208

REPOSITORIES: GEO

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Genome wide profiling of Su(H) [CSL] binding in Drosophila melanogaster larval CNSs where Notch is hyperactive in neuroblasts for 24 hours

Project description:The Notch pathway is a well conserved cell to cell communication mechanism that is normally involved in many developmental processes and when aberrantly activated it leads to diseases such as cancer. One such example is the neural stem cell tumours that arise from constitutive Notch activity in Drosophila neuroblasts from the larval Central Nervous System (CNS). To investigate how hyper-activation of Notch in larval neuroblasts leads to tumours, we mapped genome-widely the regions that are bound by Su(H) (the core Notch pathway transcription factor, known as CSL in mammals). We combined these results with the profiling of upregulated mRNAs in CNSs where Notch is hyper-activated for 24h vs control CNSs and identified 127 putative direct Notch targets in the hyperplastic CNSs. Included were genes associated with the neuroblast maintenance and self-renewal programme and genes coding for temporal transcription factors, which are involved in neuroblast progression and generation of progeny with specific identity over time. Thus, Notch induces neural stem cell tumors by promoting the expression of genes that contribute to stem cell identity and by reprogramming expression of temporal factors that regulate maturity. Su(H) binding profile in Drosophila larval CNSs where Notch is constitutively active for 24 hours. In total there are 3 samples of Su(H) ChIP in Notch hyper-activated larval CNSs.

2015-12-15 | E-GEOD-68614 | biostudies-arrayexpress

Notch targets stem-cell and temporal-programming genes to orchestrate neuroblast tumours

Project description: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 127 putative direct Notch targets that were up-regulated in the hyperplastic tissue. 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. A second category contained so-called temporal transcription factors, which are involved in neuroblast progression. Normally expressed in specific time windows, several temporal transcription factors were ectopically expressed in the stem cell tumours, suggesting that Notch had reprogrammed the normal temporal hierarchy. 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 demonstrate that Notch induces neural stem cell tumors by promoting the expression of genes that contribute to stem cell identity and by reprogramming expression of temporal factors that regulate maturity.

2016-10-18 | E-MTAB-3561 | biostudies-arrayexpress

Transcriptomes of lineage-specific Drosophila neuroblasts profiled via genetic targeting and robotic sorting

Project description:A brain consists of numerous distinct neurons arising from a limited number of progenitors, called neuroblasts in Drosophila. Each neuroblast makes a specific neuronal lineage. To unravel the transcriptional networks that underlie the development of distinct neuroblast lineages, we marked and isolated lineage-specific neuroblasts for RNA sequencing. We labeled particular neuroblasts throughout neurogenesis by activating a conditional neuroblast driver in specific lineages using various intersection strategies. The targeted neuroblasts were efficiently recovered using a custom-built device for robotic single cell picking. Transcriptome analysis on the mushroom body, antennal lobe, and type II neuroblasts besides non-selective neuroblasts, neurons, and glia revealed a rich repertoire of transcription factors expressed among neuroblasts in diverse patterns. In addition to those likely pan-neuroblast transcription factors, there exist many transcription factors selectively enriched or repressed in certain neuroblasts. The unique combinations of transcription factors present in different neuroblasts may govern the diverse lineage-specific neuron fates

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A comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing

Project description:During development, neural stem cells are temporally patterned to sequentially generate a variety of neural types before exiting the cell cycle. Temporal patterning is well-studied in Drosophila, where neural stem cells called neuroblasts sequentially express cascades of Temporal Transcription Factors (TTFs) to control the birth-order dependent neural specification. However, currently known TTFs were mostly identified through candidate antibody screening and may not be complete. In addition, many fundamental questions remain concerning the TTF cascade initiation, progression, and termination. It is also not known why temporal progression only happens in neuroblasts but not in their differentiated progeny. In this work, we performed single-cell RNA sequencing of Drosophila medulla neuroblasts of all ages to study the temporal patterning process with single-cell resolution. Our scRNA-seq data revealed that sets of genes involved in different biological processes show high to low or low to high gradients as neuroblasts age. We also identified a list of novel TTFs, and experimentally characterized their roles in the temporal progression and neural fate specification. Our study revealed a comprehensive temporal gene network that patterns medulla neuroblasts from start to end. Furthermore, we found that the progression and termination of this temporal cascade also require transcription factors differentially expressed along the differentiation axis (neuroblasts -> -> neurons). Lola proteins function as a speed modulator of temporal progression in neuroblasts; while Nerfin-1, a factor required to suppress de-differentiation in post-mitotic neurons, acts at the final temporal stage together with the last TTF of the cascade, to promote the switch to gliogenesis and the cell cycle exit. Our comprehensive study of the medulla neuroblast temporal cascade illustrated mechanisms that might be conserved in the temporal patterning of neural stem cells.

2021-12-27 | GSE168553 | GEO

Gene expression profile of supernumerary type II neuroblasts transiently overexpressing Insb

Project description:Genes that positively regulate neuroblast functional identity shoud be expressed in type II neuroblasts and become repidly downregulated in immature INPs in wild-type brains while genes that suppress neuroblast functional idnetity should be upregulated in immature INPs. The goal of this study is to identify genes involved in regulation of type II neuroblast functional identity.

2020-12-02 | GSE152636 | GEO

Transcriptome analysis of Drosophila neural stem cells reveals a transcriptional network for self-renewal.

Project description:Drosophila neuroblasts have emerged as a model for stem cell biology that is ideal for genetic analysis but is limited by the lack of cell-type specific gene expression data. Here, we describe a methodology to isolate large numbers of pure neuroblasts and differentiating neurons that retain both cell cycle and lineage characteristics. We determine transcriptional profiles by mRNA sequencing and identify 28 predicted neuroblast specific transcription factors, which can be arranged in a network containing hubs for Notch signaling, growth control and chromatin regulation. Overexpression and RNAi for these factors identify Klumpfuss as a regulator of self-renewal. We show that loss of Klu function causes premature differentiation while overexpression results in the formation of transplantable brain tumors. Our data represent a valuable resource for Drosophila developmental neurobiology and we describes methodology that can be applied to other invertebrate stem cell lineages as well. comparison of transcriptomes of Drosophila melanogaster larval neuroblasts and their differentiated daughter cells (neurons)

2012-08-21 | E-GEOD-38764 | biostudies-arrayexpress

Single-cell RNA-seq of Drosophila neuroblast tumors induced by the knockdown of prospero, E(z) and trx

Project description:COMPASS and Polycomb complexes are antagonistic chromatin complexes that are frequently inactivated in cancers, but how their inactivation affects the cellular hierarchy, composition and growth of tumors is unclear. Such characteristics can be systematically investigated in Drosophila neuroblast tumors in which cooption of temporal patterning induces a developmental hierarchy that confers cancer stem cell (CSC) properties to a subset of neuroblasts retaining an early larval temporal identity. Here, using single-cell transcriptomics, we reveal that the trithorax/MLL1/2-COMPASS-like complex guides the developmental trajectory at the top of the tumor hierarchy. Consequently, trithorax inactivation drives larval-to-embryonic temporal reversion and the dramatic expansion of CSCs that remain locked in a spectrum of early temporal states. Surprisingly, this phenotype is amplified by concomitant inactivation of Polycomb Repressive Complex 2 genes, unleashing tumor growth. This study exemplifies how inactivation of specific COMPASS and Polycomb complexes cooperates to impair tumor hierarchies and induce CSC plasticity and heterogeneity.

2021-08-31 | GSE179154 | GEO

Single-cell RNA-seq analysis of Drosophila neuroblast tumors

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2019-10-10 | GSE114986 | GEO

Ecdysone and Mediator trigger a metabolic switch uncoupling cell cycle from cell growth to end proliferation in Drosophila neural stem cells

Project description:Stem cells are highly abundant and proliferate rapidly 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 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 cell cycle progression from cell growth. This results in a progressive reduction in neuroblast cell size and ultimately in terminal differentiation. Neuroblasts isolated from brain tumors fail to undergo this shrinkage process and this may explain why they are immortalized. Our findings show that cell size control can be modified by systemic hormonal signaling and reveal a unique connection between metabolism and proliferation control in stem cells. Comparison of transcriptomes of Drosophila melanogaster central brain NBs from wild-type larval NBs, wild type pupal NBs and med27 RNAi pupal NBs.

2014-08-14 | E-GEOD-53265 | biostudies-arrayexpress

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