scholarly journals Temporal patterning in neural progenitors: from Drosophila development to childhood cancers

2020 ◽  
Vol 13 (7) ◽  
pp. dmm044883 ◽  
Author(s):  
Cédric Maurange
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cancer Susceptibility ◽  
Pediatric Brain Tumors ◽  
Neural Progenitors ◽  
Childhood Cancers ◽  
Temporal Patterning ◽  
Underlying Mechanisms ◽  
Cellular Hierarchy ◽  
Pediatric Brain

ABSTRACTThe developing central nervous system (CNS) is particularly prone to malignant transformation, but the underlying mechanisms remain unresolved. However, periods of tumor susceptibility appear to correlate with windows of increased proliferation, which are often observed during embryonic and fetal stages and reflect stereotypical changes in the proliferative properties of neural progenitors. The temporal mechanisms underlying these proliferation patterns are still unclear in mammals. In Drosophila, two decades of work have revealed a network of sequentially expressed transcription factors and RNA-binding proteins that compose a neural progenitor-intrinsic temporal patterning system. Temporal patterning controls both the identity of the post-mitotic progeny of neural progenitors, according to the order in which they arose, and the proliferative properties of neural progenitors along development. In addition, in Drosophila, temporal patterning delineates early windows of cancer susceptibility and is aberrantly regulated in developmental tumors to govern cellular hierarchy as well as the metabolic and proliferative heterogeneity of tumor cells. Whereas recent studies have shown that similar genetic programs unfold during both fetal development and pediatric brain tumors, I discuss, in this Review, how the concept of temporal patterning that was pioneered in Drosophila could help to understand the mechanisms of initiation and progression of CNS tumors in children.

scholarly journals Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity

2019 ◽  
Author(s):  
Anthony M. Rossi ◽  
Claude Desplan
Keyword(s):  
Mushroom Body ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neural Progenitors ◽  
Neuronal Diversity ◽  
Temporal Patterning ◽  
Activin Signaling ◽  
Extrinsic Cues ◽  
Neuronal Types ◽  
Temporal Program

SummaryTemporal patterning of neural progenitors leads to the sequential production of diverse neuronal types. To better understand how extrinsic cues interact with intrinsic temporal programs to contribute to temporal patterning, we studied the Drosophila mushroom body neural progenitors (neuroblasts). Each of these four neuroblasts divides ~250 times to sequentially produce only three main neuronal types over the course of ~9 days of development: γ, followed by α’β’, and finally αβ neurons. The intrinsic temporal clock is composed of two RNA-binding proteins, IGF-II mRNA binding protein (Imp) and Syncrip (Syp), that are expressed in opposing temporal gradients. Activin signaling affects the production of α’β’ neurons but whether and how this extrinsic cue interacts with the intrinsic temporal program was not known. We show that the Activin ligand Myoglianin produced from glia regulates the levels of the intrinsic temporal factor Imp in mushroom body neuroblasts. In neuroblasts mutant for the Activin signaling receptor baboon, Imp levels are higher than normal during the α’β’ temporal window, leading to the specific loss of the α’β’ neurons. The intrinsic temporal clock still progresses but with a delay, skipping the α’β’ window without affecting the total number of neurons produced: The number of γ neurons increases, α’β’ disappear and the number of αβ neurons decreases. Our results illustrate that an extrinsic cue modifies an intrinsic temporal program to increase neuronal diversity.

Expression of the Neural RNA-Binding Protein Musashi1 in Pediatric Brain Tumors

2007 ◽  
Vol 43 (4) ◽  
pp. 279-284 ◽  
Author(s):  
Aya Nakano ◽  
Yonehiro Kanemura ◽  
Kanji Mori ◽  
Eri Kodama ◽  
Atsuyo Yamamoto ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Pediatric Brain Tumors ◽  
Pediatric Brain

CELF1 Promotes Matrix Metalloproteinases Gene Expression at Transcriptional Level in Lens Epithelial Cells

2021 ◽  
Author(s):  
Jun Xiao ◽  
Xi Tian ◽  
Siyan Jin ◽  
Yanhui He ◽  
Meijiao Song ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Epithelial Cells ◽  
Matrix Metalloproteinases ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Lens Epithelial Cells ◽  
Transcriptional Level ◽  
Rna Seq ◽  
Whole Transcriptome Sequencing ◽  
Underlying Mechanisms

Abstract Background: RNA binding proteins (RBPs)-mediated regulation plays important roles in many eye diseases, including the canonical RBP CELF1 in cataract. While the definite molecular regulatory mechanisms of CELF1 on cataract still remain elusive. Methods: In this study, we overexpressed CELF1 in lens epithelial SRA01/04 cells and applied whole transcriptome sequencing (RNA-seq) method to analyze the global differences mediated by CELF1. We then analyzed public RNA-seq and CELF1-RNA interactome data to decipher the underlying mechanisms.Results: The results showed that transcriptome profile was globally changed by CELF1 overexpression (CELF1-OE). Functional analysis revealed CELF1 specifically increased the expression of genes in extracellular matrix disassembly, extracellular matrix organization, and proteolysis, which could be classified into matrix metalloproteinases (MMPs) family. This finding was also validated by RT-qPCR and public mouse early embryonic lens data. Integrating analysis with public CELF1-RNA interactome data revealed that no obvious CELF1-binding peak was found on the transcripts of these genes, indicating an indirectly regulatory role of CELF1 in lens epithelial cells. Conclusions: Our study demonstrated that CELF1-OE promotes transcriptional level of MMP genes; and this regulation may be completed by other ways except for binding to RNA targets. These results suggest that CELF1-OE is implicated in the development of lens, which is associated with cataract and expands our understanding of CELF1 regulatory roles as an RNA binding protein.

scholarly journals Nanos promotes epigenetic reprograming of the germline by down-regulation of the THAP transcription factor LIN-15B

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Chih-Yung Sean Lee ◽  
Tu Lu ◽  
Geraldine Seydoux
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Transcriptional Activation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Primordial Germ Cells ◽  
Germline Development ◽  
C Elegans ◽  
Maternal Transcripts ◽  
Underlying Mechanisms

Nanos RNA-binding proteins are required for germline development in metazoans, but the underlying mechanisms remain poorly understood. We have profiled the transcriptome of primordial germ cells (PGCs) lacking the nanos homologs nos-1 and nos-2 in C. elegans. nos-1nos-2 PGCs fail to silence hundreds of transcripts normally expressed in oocytes. We find that this misregulation is due to both delayed turnover of maternal transcripts and inappropriate transcriptional activation. The latter appears to be an indirect consequence of delayed turnover of the maternally-inherited transcription factor LIN-15B, a synMuvB class transcription factor known to antagonize PRC2 activity. PRC2 is required for chromatin reprogramming in the germline, and the transcriptome of PGCs lacking PRC2 resembles that of nos-1nos-2 PGCs. Loss of maternal LIN-15B restores fertility to nos-1nos-2 mutants. These findings suggest that Nanos promotes germ cell fate by downregulating maternal RNAs and proteins that would otherwise interfere with PRC2-dependent reprogramming of PGC chromatin.

scholarly journals Insights Into circRNAs: Functional Roles in Lung Cancer Management and the Potential Mechanisms

2021 ◽  
Vol 9 ◽  
Author(s):  
Bing Feng ◽  
Hao Zhou ◽  
Ting Wang ◽  
Xinrong Lin ◽  
Yongting Lai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Large Body ◽  
Circular Rnas ◽  
Functional Roles ◽  
Cancer Management ◽  
Novel Biomarkers ◽  
Mirna Sponges ◽  
Underlying Mechanisms

Lung cancer is the most prevalent cancer globally. It is also the leading cause of cancer-related death because of the late diagnosis and the frequent resistance to therapeutics. Therefore, it is impending to identify novel biomarkers and effective therapeutic targets to improve the clinical outcomes. Identified as a new class of RNAs, circular RNAs (circRNAs) derive from pre-mRNA back splicing with considerable stability and conservation. Accumulating research reveal that circRNAs can function as microRNA (miRNA) sponges, regulators of gene transcription and alternative splicing, as well as interact with RNA-binding proteins (RBPs), or even be translated into proteins directly. Currently, a large body of circRNAs have been demonstrated differentially expressed in physiological and pathological processes including cancer. In lung cancer, circRNAs play multiple roles in carcinogenesis, development, and response to different therapies, indicating their potential as diagnostic and prognostic biomarkers as well as novel therapeutics. In this review, we summarize the multi-faceted functions of circRNAs in lung cancer and the underlying mechanisms, together with the possible future of these discoveries in clinical application.

scholarly journals Cooption of antagonistic RNA-binding proteins establishes cell hierarchy in Drosophila neuro-developmental tumors

2018 ◽  
Author(s):  
Sara Genovese ◽  
Raphaël Clément ◽  
Cassandra Gaultier ◽  
Florence Besse ◽  
Karine Narbonne-Reveau ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stochastic Modelling ◽  
Clonal Analysis ◽  
Neural Progenitors ◽  
Hierarchical Organization ◽  
Self Renewal ◽  
Intermediate Progenitors

AbstractThe mechanisms that govern the hierarchical organization of tumors are still poorly understood, especially in highly heterogeneous neural cancers. Previously, we had shown that aggressive neural tumors can be induced upon dedifferentiation of susceptible intermediate progenitors produced during early development (Narbonne-Reveau et al., 2016). Using clonal analysis, stochastic modelling and single-cell transcriptomics, we now find that such tumors rapidly become heterogeneous, containing progenitors with different proliferative potentials. We demonstrate that tumor heterogeneity emerges from the deregulated transition between two antagonistic RNA-binding proteins, Imp and Syncrip, that switch neural progenitors from a default self-renewing to a differentiation-prone state during development. Consequently, aberrant maintenance of Imp confers a cancer stem cell-like identity as Imp+ progenitors sustain tumor growth while being able to continuously generate Syncrip+ progenitors. The latter exhibit limited self-renewal likely due to Syncrip-mediated metabolic exhaustion. This study provides an example of how a subverted developmental transition establishes a hierarchical tumor.

scholarly journals Stem cell intrinsic, Seven-up-triggered temporal factor gradients diversify intermediate neural progenitors

2017 ◽  
Author(s):  
Qingzhong Ren ◽  
Ching-Po Yang ◽  
Zhiyong Liu ◽  
Ken Sugino ◽  
Kent Mok ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neural Progenitors ◽  
Small Range ◽  
Type Ii ◽  
Genetic Manipulations ◽  
Temporal Windows ◽  
Number Of Cells ◽  
Temporal Factor

SummaryDrosophila type II neuroblasts produce numerous neurons and glia due to transiently amplifying, intermediate neural progenitors (INP). Consecutively born INPs produce morphologically distinct progeny, presumably due to temporal patterning in type II neuroblasts. We therefore profiled type II neuroblasts’ transcriptome across time. Our results reveal opposing temporal gradients of Imp and Syp RNA-binding proteins (descending and ascending, respectively). Maintaining Imp expression throughout brain development expands the number of neurons/glia with early temporal fate at the expense of cells with late fate. Conversely, precocious upregulation of Syp reduces the number of cells with early fate. Further, we reveal that the transcription factor, Seven-up initiates progression of the Imp/Syp gradients. Interestingly, genetic manipulations that fix Imp or Syp levels still yield progeny with a small range of early fates. We propose that the Seven-up-initiated Imp/Syp gradients create coarse temporal windows within type II neuroblasts to pattern INPs, which subsequently undergo fine-tuned subtemporal patterning.

scholarly journals Isoform-specific regulation of rhythmic gene expression by alternative polyadenylation

2020 ◽  
Author(s):  
Ben J Greenwell ◽  
Joshua R Beytebiere ◽  
Teresa M Lamb ◽  
Deborah Bell-Pedersen ◽  
Christine Merlin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Active Phase ◽  
Specific Expression ◽  
Rhythmic Expression ◽  
Rhythmic Gene ◽  
Specific Regulation ◽  
Underlying Mechanisms

Alternative polyadenylation (APA) generates transcript isoforms with different 3′ ends. Differences in polyadenylation sites usage, which have been associated with diseases like cancer, regulate mRNA stability, subcellular localization, and translation. By characterizing APA across the 24-hour day in mouse liver, here we show that rhythmic gene expression occurs largely in an APA isoform-specific manner, and that hundreds of arrhythmically expressed genes surprisingly exhibit a rhythmic APA isoform. The underlying mechanisms comprise isoform-specific post-transcriptional regulation, transcription factor driven expression of specific isoform, co-transcriptional recruitment of RNA binding proteins that regulate mRNA cleavage and polyadenylation, and, to a lesser extent, cell subtype-specific expression. Remarkably, rhythmic expression of specific APA isoforms generates 24-hour rhythms in 3′ UTR length, with shorter UTRs in anticipation of the mouse active phase. Taken together, our findings demonstrate that cycling transcriptomes are regulated by APA, and suggest that APA strongly impacts the rhythmic regulation of biological functions.

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