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.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Anthony M Rossi ◽  
Claude Desplan
Keyword(s):  
Mushroom Body ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Diversity ◽  
Temporal Window ◽  
Activin Signaling ◽  
Extrinsic Cues ◽  
Neuronal Types ◽  
Intrinsic Program ◽  
Temporal Program

Temporal patterning of neural progenitors leads to the sequential production of diverse neurons. To understand how extrinsic cues influence intrinsic temporal programs, we studied Drosophila mushroom body progenitors (neuroblasts) that sequentially produce only three neuronal types: γ, then α’β’, followed by αβ. Opposing gradients of two RNA-binding proteins Imp and Syp comprise the intrinsic temporal program. Extrinsic activin signaling regulates the production of α’β’ neurons but whether it affects the intrinsic temporal program was not known. We show that the activin ligand Myoglianin from glia regulates the temporal factor Imp in mushroom body neuroblasts. Neuroblasts missing the activin receptor Baboon have a delayed intrinsic program as Imp is higher than normal during the α’β’ temporal window, causing the loss of α’β’ neurons, a decrease in αβ neurons, and a likely increase in γ neurons, without affecting the overall number of neurons produced. Our results illustrate that an extrinsic cue modifies an intrinsic temporal program to increase neuronal diversity.

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 Mamo decodes hierarchical temporal gradients into terminal neuronal fate

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ling-Yu Liu ◽  
Xi Long ◽  
Ching-Po Yang ◽  
Rosa L Miyares ◽  
Ken Sugino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Diversity ◽  
Temporal Expression ◽  
Identity Maintenance ◽  
Temporal Gene Expression ◽  
Neuronal Fate ◽  
Mammalian Genes ◽  
Post Transcriptional Regulation

Temporal patterning is a seminal method of expanding neuronal diversity. Here we unravel a mechanism decoding neural stem cell temporal gene expression and transforming it into discrete neuronal fates. This mechanism is characterized by hierarchical gene expression. First, Drosophila neuroblasts express opposing temporal gradients of RNA-binding proteins, Imp and Syp. These proteins promote or inhibit chinmo translation, yielding a descending neuronal gradient. Together, first and second-layer temporal factors define a temporal expression window of BTB-zinc finger nuclear protein, Mamo. The precise temporal induction of Mamo is achieved via both transcriptional and post-transcriptional regulation. Finally, Mamo is essential for the temporally defined, terminal identity of α’/β’ mushroom body neurons and identity maintenance. We describe a straightforward paradigm of temporal fate specification where diverse neuronal fates are defined via integrating multiple layers of gene regulation. The neurodevelopmental roles of orthologous/related mammalian genes suggest a fundamental conservation of this mechanism in brain development.

scholarly journals Complexity and graded regulation of neuronal cell type-specific alternative splicing revealed by single-cell RNA sequencing

2021 ◽  
Author(s):  
Huijuan Feng ◽  
Daniel F. Moakley ◽  
Shuonan Chen ◽  
Melissa G. McKenzie ◽  
Vilas Menon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Neuronal Cell ◽  
Cell Types ◽  
Mammalian Brain ◽  
Differential Splicing ◽  
Hierarchical Levels ◽  
Neuronal Types ◽  
And Function

AbstractThe enormous neuronal cellular diversity in the mammalian brain, which is highly prototypical and organized in a hierarchical manner, is dictated by cell type-specific gene regulatory programs at the molecular level. Although prevalent in the brain, contribution of alternative splicing (AS) to the molecular diversity across neuronal cell types is just starting to emerge. Here we systematically investigated AS regulation across over 100 transcriptomically defined neuronal types of the adult mouse cortex using deep single cell RNA-sequencing (scRNA-seq) data. We found distinct splicing programs between glutamatergic and GABAergic neurons and between subclasses within each neuronal class, consisting of overlapping sets of alternative exons showing differential splicing at multiple hierarchical levels. Using an integrative approach, our analysis suggests that RNA-binding proteins (RBPs) Celf1/2, Mbnl2 and Khdrbs3 are preferentially expressed and more active in glutamatergic neurons, while Elavl2 and Qk are preferentially expressed and more active in GABAergic neurons. Importantly, these and additional RBPs also contribute to differential splicing between neuronal subclasses at multiple hierarchical levels, and some RBPs drive splicing dynamics that do not conform to the hierarchical structure defined by the transcriptional profiles. Thus, our results suggest graded regulation of AS across neuronal cell types, which provides a molecular mechanism orthogonal to, rather than downstream of, transcriptional regulation in specifying neuronal identity and function.SignificanceAlternative splicing (AS) is extensively used in the mammalian brain, but its contribution to the molecular and cellular diversity across neuronal cell types remains poorly understood. Through systematic and integrative analysis of AS regulation across over 100 transcriptomically defined cortical neuronal types, we found neuronal subclass-specific splicing regulatory programs consists of overlapping alternative exons showing differential splicing at multiple hierarchical levels. This graded AS regulation is controlled by unique combinations of RNA-binding proteins (RBPs). Importantly, these RBPs also drive splicing dynamics across neuronal cell types that do not conform to the hierarchical taxonomy established based on transcriptional profiles, suggesting that the graded AS regulation provides a molecular mechanism orthogonal to transcriptional regulation in specifying neuronal identity and function.

scholarly journals Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Max Koppers ◽  
Roberta Cagnetta ◽  
Toshiaki Shigeoka ◽  
Lucia CS Wunderlich ◽  
Pedro Vallejo-Ramirez ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Retinal Ganglion ◽  
Local Translation ◽  
Surface Receptors ◽  
Guidance Cue ◽  
Extrinsic Cues ◽  
Selective Translation ◽  
Specific Mrnas

Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.

scholarly journals A comprehensive series of temporal transcription factors in the fly visual system

2021 ◽  
Author(s):  
Nikolaos Konstantinides ◽  
Anthony M. Rossi ◽  
Aristides Escobar ◽  
Liébaut Dudragne ◽  
Yen-Chung Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Single Cell ◽  
Neuronal System ◽  
Neuronal Diversity ◽  
Temporal Patterning ◽  
Neuronal Stem Cells ◽  
Mrna Sequencing ◽  
Neuronal Types ◽  
Cell Type Specific

AbstractThe brain consists of thousands of different neuronal types that are generated through multiple divisions of neuronal stem cells. These stem cells have the capacity to generate different neuronal types at different stages of their development. In Drosophila, this temporal patterning is driven by the successive expression of temporal transcription factors (tTFs). While a number of tTFs are known in different animals and across various parts of the nervous system, these have been mostly identified by informed guesses and antibody availability. We used single-cell mRNA sequencing to identify the complete series of tTFs that specify most Drosophila medulla neurons in the optic lobe. We tested the genetic interactions among these tTFs. While we verify the general principle that tTFs regulate the progression of the series by activating the next tTFs in the series and repressing the previous ones, we also identify more complex regulations. Two of the tTFs, Eyeless and Dichaete, act as hubs integrating the input of several upstream tTFs before allowing the series to progress and in turn regulating the expression of several downstream tTFs. Moreover, we show that tTFs not only specify neuronal identity by controlling the expression of cell type-specific genes. Finally, we describe the very first steps of neuronal differentiation and find that terminal differentiation genes, such as neurotransmitter-related genes, are present as transcripts, but not as proteins, in immature larval neurons days before they are being used in functioning neurons; we show that these mechanisms are conserved in humans. Our results offer a comprehensive description of a temporal series of tTFs in a neuronal system, offering mechanistic insights into the regulation of the progression of the series and the regulation of neuronal diversity. This represents a proof-of-principle for the use of single-cell mRNA sequencing for the comparison of temporal patterning across phyla that can lead to an understanding of how the human brain develops and how it has evolved.

scholarly journals Temporal patterning of the central nervous system by a shared transcription factor code

2020 ◽  
Author(s):  
Andreas Sagner ◽  
Isabel Zhang ◽  
Thomas Watson ◽  
Jorge Lazaro ◽  
Manuela Melchionda ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Diversity ◽  
Temporal Patterning ◽  
Tgfβ Signalling ◽  
The Central Nervous System ◽  
Neuronal Subtype ◽  
Factor Code ◽  
Temporal Program

AbstractThe molecular mechanisms that ensure the reproducible generation of neuronal diversity in the vertebrate nervous system are incompletely understood. Here we provide evidence of a temporal patterning program consisting of cohorts of transcription factors expressed in neurons generated at successive developmental timepoints. This program acts in parallel to spatial patterning, diversifying neurons throughout the nervous system and in neurons differentiated in-vitro from stem cells. We demonstrate the TGFβ signalling pathway controls the pace of the temporal program. Furthermore, targeted perturbation of components of the temporal program, Nfia and Nfib, reveals their requirement for the generation of late-born neuronal subtypes. Together, our results provide evidence for the existence of a previously unappreciated global temporal program of neuronal subtype identity and suggest that the integration of spatial and temporal patterning programs diversifies and organises neuronal subtypes in the vertebrate nervous system.

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.

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