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Neuroectoderm specification and neuroblast formation. (a) A schematic cross-section through a Drosophila embryo. The genes ventral nervous system defective (vnd ), intermediate neuroblast defective (ind ) and muscle segment homeobox (msh) pattern the neuroectoderm in three columnar domains in response to antagonistic morphogenetic gradients of Dpp and Sog. (b) Single cells are selected to acquire a neuroblast fate from a proneural equivalence group of five to six cells. This is achieved by the process of lateral inhibition and is based on a molecular regulatory loop between the adjacent cells. The selected neuroblast enlarges and delaminates basally into the embryo. The remaining cells of each proneural cluster adopt an alternative epidermal fate. After delamination, each neuroblast begins to divide asymmetrically in a stem cell-like manner along the apico-basal axis. (c) A simplified scheme of lateral inhibition involving Notch, Delta and the proneural genes. Activation of the Notch signalling cascade by the Delta ligand leads to repression of proneural gene expression in the presumptive nonneural cell. Since Delta expression is regulated by proneural transcription factors, downregulation of proneural genes leads to a reduction in Notch activation in the neighbouring cell. As a result, proneural gene activity is maintained in the presumptive neuroblast and repressed in its neighbours.
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Drosophila neuroblasts are similar to mammalian neural stem cells in their ability to self-renew and to produce many different types of neurons and glial cells. In the past two decades, great advances have been made in understanding the molecular mechanisms underlying embryonic neuroblast formation, the establishment of cell polarity and the tempor...
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Drosophila melanogaster neural stem cells (neuroblasts [NBs]) divide asymmetrically by differentially segregating protein determinants into their daughter cells. Although the machinery for asymmetric protein segregation is well understood, the events that reprogram one of the two daughter cells toward terminal differentiation are less clear. In thi...
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... Such distinct regulation of mRNAs with rare codons mirrors other unique aspects of mRNA regulation in neural cells, including splicing [42][43][44] , RNA modifications 45,46 , and polyadenylation 47,48 . Drosophila larvae have a well-characterized neural stem cell lineage 5,[49][50][51][52] , making the fly larval brain a well-suited system to explore dynamic codon usage regulation during neural differentiation. ...
... Using an antibody for the NB-specific transcription factor Deadpan (Dpn) 64 , we find that GFP-rare b is not expressed in NBs, while GFP-common is ( Fig. 1E vs F). NBs divide asymmetrically to self-renew and produce another type of progenitor cell, ganglion mother cells (GMCs) 5,[49][50][51][52]65,66 . Using earmuff-GAL4 to drive a membrane-targeted UAS-tdTomato protein specifically in GMCs 67 , we find GFP-rare b protein is again not expressed, while GFPcommon is expressed (Fig. 1G vs H). ...
Regulation of codon optimality is an increasingly appreciated layer of cell- and tissue-specific protein expression control. Here, we use codon-modified reporters to show that differentiation of Drosophila neural stem cells into neurons enables protein expression from rare-codon-enriched genes. From a candidate screen, we identify the cytoplasmic polyadenylation element binding (CPEB) protein Orb2 as a positive regulator of rare-codon-dependent mRNA stability in neurons. Using RNA sequencing, we reveal that Orb2-upregulated mRNAs in the brain with abundant Orb2 binding sites have a rare-codon bias. From these Orb2-regulated mRNAs, we demonstrate that rare-codon enrichment is important for mRNA stability and social behavior function of the metabotropic glutamate receptor (mGluR). Our findings reveal a molecular mechanism by which neural stem cell differentiation shifts genetic code regulation to enable critical mRNA stability and protein expression.
... It is further subdivided into three longitudinal domains: lateral, intermediate, and medial. This subdivision arises from the gradients of dpp (decapentaplegic) and sog (short of gastrulation), and through the influence of Epidermal Growth Factor Receptor (EGFR) signaling (Egger et al., 2008). In this tissue, esg is expressed in both the medial and lateral columns, while it remains repressed in the intermediate column. ...
... Just after germ band extension and before germ band retraction (embryonic stages 8-11) NBs delaminate from the neuroectoderm and undergo asymmetric divisions, where one of the daughter cells renews as a stem cell, while the other produces a daughter cell known as ganglion mother cell (GMC). The GMC subsequently undergoes one more division to generate two post-mitotic cells, which can differentiate into either neurons or glial cells (Egger et al., 2008). During the asymmetric division of these NBs, cell fate determinants like Prospero (Pros) are segregated basally within the NB and inherited by the daughter cell which becomes the GMC. ...
The Snail superfamily of transcription factors plays a crucial role in metazoan development; one of the most important vertebrate members of this family is Snai1 which is orthologous to the Drosophila melanogaster esg gene. This review offers a comprehensive examination of the roles of the esg gene in Drosophila development, covering its expression pattern and downstream targets, and draws parallels between the vertebrate Snai1 family proteins on controlling the epithelial‐to‐mesenchymal transition and esg . This gene regulates stemness, ploidy, and pluripontency. esg is expressed in various tissues during development, including the gut, imaginal discs, and neuroblasts. The functions of the esg include the suppression of differentiation in intestinal stem cells and the preservation of diploidy in imaginal cells. In the nervous system development, esg expression also inhibits neuroblast differentiation, thus regulating the number of neurons and the moment in development of neuronal differentiation. Loss of esg function results in diverse developmental defects, including defects in intestinal stem cell maintenance and differentiation, and alters imaginal disc and nervous system development. Expression levels of esg also play a role in regulating longevity and metabolism in adult stages. This review provides an overview of the current understanding of esg's developmental role, emphasizing cellular and tissue effects that arise from its loss of function. The insights gained may contribute to a better understanding of evolutionary conserved developmental mechanisms and certain metabolic diseases.
... In addition to NSC-like properties such as expressing Dpn, brat tumour cells are larger compared to non-tumour counterparts (Betschinger et al, 2006;Bowman et al, 2008). At 24 h ALH, NSCs measure 7-8 µm while INP size is 4-6 µm in non-tumour controls (Ding et al, 2016;Egger et al, 2008;Gil-Ranedo et al, 2019). We found that already at this early stage there is a reduced number of smaller cells (<5 µm) and increased number of larger cells in brat depleted lineages, demonstrating enlarged TIC size prior to overproliferation onset (Fig. 2F,H,K). ...
Cell commitment to tumourigenesis and the onset of uncontrolled growth are critical determinants in cancer development but the early events directing tumour initiating cell (TIC) fate remain unclear. We reveal a single-cell transcriptome profile of brain TICs transitioning into tumour growth using the brain tumour ( brat ) neural stem cell-based Drosophila model. Prominent changes in metabolic and proteostasis-associated processes including ribogenesis are identified. Increased ribogenesis is a known cell adaptation in established tumours. Here we propose that brain TICs boost ribogenesis prior to tumour growth. In brat- deficient TICs, we show that this dramatic change is mediated by upregulated HEAT-Repeat Containing 1 ( HEATR1 ) to promote ribosomal RNA generation, TIC enlargement and onset of overgrowth. High HEATR1 expression correlates with poor glioma patient survival and patient-derived glioblastoma stem cells rely on HEATR1 for enhanced ribogenesis and tumourigenic potential. Finally, we show that HEATR1 binds the master growth regulator MYC, promotes its nucleolar localisation and appears required for MYC-driven ribogenesis, suggesting a mechanism co-opted in ribogenesis reprogramming during early brain TIC development.
... Adult cell numbers in these lineages are therefore determined by the number of rounds of neuroblast and IPC division. Hence, by adding a second proliferative phase IPCs increase the final number of neurons produced by neuroblasts [14][15][16][17]. Nervous systems in insects are extremely diverse in their size, structure and ontogenetic trajectories [18,19]. ...
The study of neurogenesis is critical to understanding of the evolution of nervous systems. Within invertebrates, this process has been extensively studied in Drosophila melanogaster , which is the predominant model thanks to the availability of advanced genetic tools. However, insect nervous systems are extremely diverse, and by studying a range of taxa we can gain additional information about how nervous systems and their development evolve. One example of the high diversity of insect nervous system diversity is provided by the mushroom bodies. Mushroom bodies have critical roles in learning and memory and vary dramatically across species in relative size and the type(s) of sensory information they process. Heliconiini butterflies provide a useful snapshot of this diversity within a closely related clade. Within Heliconiini, the genus Heliconius contains species where mushroom bodies are 3–4 times larger than other closely related genera, relative to the rest of the brain. This variation in size is largely explained by increases in the number of Kenyon cells, the intrinsic neurons which form the mushroom body. Hence, variation in mushroom body size is the product of changes in cell proliferation during Kenyon cell neurogenesis. Studying this variation requires adapting labelling techniques for use in less commonly studied organisms, as methods developed for common laboratory insects often do not work. Here, we present a modified protocol for EdU staining to examine neurogenesis in large-brained insects, using Heliconiini butterflies as our primary case, but also demonstrating applicability to cockroaches, another large-brained insect.
... In stem cell homeostasis, fate asymmetry is achieved, in which a half of the daughter cells from the entire stem cell population is retained as stem cells and the other half is directed toward differentiation. To date, two distinct models have been suggested to explain the mechanisms of stem cell homeostasis, i.e., how the cell fate asymmetry is achieved 4,5 : the hierarchical model and the neutral competition (NC) model. However, the mechanisms of stem cell homeostasis in many species and tissues remain controversial. ...
... Such asymmetry at the single-cell level achieves fate asymmetry in the entire stem cell population, where loss of stem cells by their differentiation is compensated by asymmetric division of master stem cells, ensuring the maintenance of the stem cell population. In Drosophila, stem cells in the germline and developing central nervous system have been demonstrated to undergo invariant asymmetric cell divisions, giving rise to one stem cell and one differentiating cell 4,5 , strongly supporting the hierarchical model. The model has also been considered extensively in mammalian stem cell homeostasis. ...
Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. Two distinct models have been proposed as mechanisms of stem cell homeostasis. According to the classical model, there is hierarchy among stem cells, and master stem cells produce stem cells by asymmetric division; whereas, according to the recent model, stem cells are equipotent and neutrally compete. However, the mechanism remains controversial in several tissues and species. Here, we developed a mathematical model linking the two models, named the hierarchical neutral competition (hNC) model. Our theoretical analysis showed that the combination of the hierarchy and neutral competition exhibited bursts in clonal expansion, which was consistent with experimental data of rhesus macaque hematopoiesis. Furthermore, the scaling law in clone size distribution, considered a unique characteristic of the recent model, was satisfied even in the hNC model. Based on the findings above, we proposed the criterion for distinguishing the three models based on experiments.
... Drosophila NSCs (historically called neuroblasts) are specified during embryogenesis and start proliferating to generate the neurons and glia that will form the larval CNS [16][17][18] . When these primary lineages are completed, embryonic NSCs exit the cell cycle and enter a quiescent state. ...
Neural stem cells (NSCs) live in an intricate cellular microenvironment supporting their activity, the niche. Whilst shape and function are inseparable, the morphogenetic aspects of niche development are poorly understood. Here, we use the formation of a glial niche to investigate acquisition of architectural complexity. Cortex glia (CG) in Drosophila regulate neurogenesis and build a reticular structure around NSCs. We first show that individual CG cells grow tremendously to ensheath several NSC lineages, employing elaborate proliferative mechanisms which convert these cells into syncytia rich in cytoplasmic bridges. CG syncytia further undergo homotypic cell–cell fusion, using defined cell surface receptors and actin regulators. Cellular exchange is however dynamic in space and time. This atypical cell fusion remodels cellular borders, restructuring the CG syncytia. Ultimately, combined growth and fusion builds the multi-level architecture of the niche, and creates a modular, spatial partition of the NSC population. Our findings provide insights into how a niche forms and organises while developing intimate contacts with a stem cell population.
... 40 The embryonic CNS is formed from a relatively constant number of neural stem cells, named neuroblasts, which divide asymmetrically to self-renew and differentiate into neurons and glial cells. 41,42 At the end of neurogenesis, neuroblasts shrink and enter into quiescence, ending the primary neurogenesis. [43][44][45] After hatching, larvae resume tissue growth only in response to an amino acid-rich diet, 46 which initiates a secondary wave of neurogenesis in the CNS. ...
In the wild, animals face different challenges including multiple events of food scarcity. How they overcome these conditions is essential for survival. Thus, adaptation mechanisms evolved to allow the development and survival of an organism during nutrient restriction periods. Given the high energy demand of the nervous system, the molecular mechanisms of adaptation to malnutrition are of great relevance to fuel the brain. The blood-brain barrier (BBB) is the interface between the central nervous system (CNS) and the circulatory system. The BBB mediates the transport of macromolecules in and out of the CNS, and therefore, it can buffer changes in nutrient availability. In this review, we collect the current evidence using the fruit fly, Drosophila melanogaster, as a model of the role of the BBB in the adaptation to starvation. We discuss the role of the Drosophila BBB during nutrient deprivation as a potential sensor for circulating nutrients, and transient nutrient storage as a regulator of the CNS neurogenic niche.
... During Drosophila embryonic neurogenesis, the nervous system required for larval life is generated ( Fig 1A) [45][46][47]. Larvae then develop through three instar stages (L1-L3) before they pupate and become adults. During larval life, a second wave of neurogenesis occurs, and about 90% of adult neurons are created [48]. ...
... Our knockdowns and rescues are limited to neuronal stem cells and their immature progeny. Drosophila neuronal stem cells progress through a cascade of transcriptionally distinct identities before permanently differentiating or dying [45,46,61]. During division, this developmental cascade leads to a diversity of developmentally plastic immature daughter cells that undergo further pre-and post-transcriptionally regulated maturation steps, which precede the formation of synapses and ultimately action potentials. ...
Spinal muscular atrophy (SMA) is the most common autosomal recessive neurodegenerative disease, and is characterised by spinal motor neuron loss, impaired motor function and, often, premature death. Mutations and deletions in the widely expressed survival motor neuron 1 ( SMN1 ) gene cause SMA; however, the mechanisms underlying the selectivity of motor neuron degeneration are not well understood. Although SMA is degenerative in nature, SMN function during embryonic and early postnatal development appears to be essential for motor neuron survival in animal models and humans. Notwithstanding, how developmental defects contribute to the subversion of postnatal and adult motor function remains elusive. Here, in a Drosophila SMA model, we show that neurodevelopmental defects precede gross locomotor dysfunction in larvae. Furthermore, to specifically address the relevance of SMN during neurogenesis and in neurogenic cell types, we show that SMN knockdown using neuroblast-specific and pan-neuronal drivers, but not differentiated neuron or glial cell drivers, impairs adult motor function. Using targeted knockdown, we further restricted SMN manipulation in neuroblasts to a defined time window. Our aim was to express specifically in the neuronal progenitor cell types that have not formed synapses, and thus a time that precedes neuromuscular junction formation and maturation. By restoring SMN levels in these distinct neuronal population, we partially rescue the larval locomotor defects of Smn mutants. Finally, combinatorial SMN knockdown in immature and mature neurons synergistically enhances the locomotor and survival phenotypes. Our in-vivo study is the first to directly rescue the motor defects of an SMA model by expressing Smn in an identifiable population of Drosophila neuroblasts and developing neurons, highlighting that neuronal sensitivity to SMN loss may arise before synapse establishment and nerve cell maturation.
... Proneural clusters initiate a selection process based on reciprocal signaling referred to as lateral inhibition that selects one cell from each cluster as a neuroblast, whereas the remaining cells will become part of the epidermis (epidermoblasts) (Hartenstein and Wodarz 2013). Lateral inhibition involves Delta-Notch signaling between adjacent cells, where the eventual neuroblast at the arrangement's center inhibits the surrounding cells from adopting a neurogenic fate while reinforcing its own identity (Arefin et al. 2019;Hartenstein and Wodarz 2013;Egger, Chell, and Brand 2008) (for more details see section 5.3.1). In each hemi-segment, a total of ~30 neuroblasts delaminate over a total of five delamination waves across Drosophila embryonic development starting at developmental stage 8 and lasting until stage 11. ...
... central nervous system and analogous in function to the spinal cord in vertebrates. (Hartenstein and Wodarz 2013;Egger, Chell, and Brand 2008). ...
... Lin and Lee 2012), as well as a temporal cascade of transcription factors that -as far as we know -most of the ventral nerve cord neuroblasts progress through after delamination. This cascades initiates with the expression of hunchback (hb), which initiates Krueppel (Kr), which initiates paired domain (pdm), which initiates Castor (Cas) (Hb→Kr→Pdm→Cas) (Egger, Chell, and Brand 2008). Additionally, at least Pdm and Cas repress earlier genes in this cascade, promoting the lineage progression. ...
Die embryonale Neurogenese in Drosophila ist eine hochgradig koordinierte Abfolge von Zellschicksalsentscheidungen, die viele Ähnlichkeiten mit der Entwicklung des Nervensystems in Wirbeltieren aufweist. Diese Zellschicksalsentscheidungen sind räumlich und zeitlich koordiniert. Diese Zellen entstehen an stereotypen Positionen in jedem Segment und sind entlang zweier räumlicher Achsen angeordnet: der dorsoventralen und der anteroposterioren Achse. Neuroblasten teilen sich, um stereotype Zelllinien zu bilden, und die Zellen weisen charakteristische Zellmorphologien und -ziele auf, wobei die molekularen Mechanismen, die diese Merkmale bestimmen, noch weitgehend unbekannt sind. Jahrzehnte der Genetik haben einige Faktoren aufgedeckt, die für viele dieser Entscheidungen notwendig sind, aber ein Verständnis der einzelnen neurogenen Linien auf Genomebene war bis vor kurzem in vivo unmöglich. Ich habe mRNA aus Einzelzellen verwendet, um die Transkriptomdynamik von Schicksalsentscheidungen in der frühen Entwicklung des Nervensystems zu untersuchen. Mein Ziel ist es, zu entschlüsseln, wie sich Zellen unterscheiden, wenn Entscheidungen getroffen werden, die für die Entwicklung des Nervensystems wesentlich sind. Ich habe Transkriptomdaten von einzelnen Zellen aus Zehntausenden von Neuroblasten während der gesamten embryonalen Neurogenese erstellt. Es gelang mir, spezifische neurogene Populationen und ihre Genexpressionsprofile entlang ihrer Differenzierungswege zu identifizieren. Ich konnte die komplizierten zeitlichen Achsen, die das sich entwickelnde embryonale Nervensystem formen, teilweise entschlüsseln - ein Prozess, der von der Fliege bis zum Menschen konserviert ist. Diese Arbeit hat die Identifizierung lokalisierter Marker und sogar spezifischer Neuroblasten ermöglicht. Dieses Verständnis kann nun mit Informationen über die einzelnen Zellschicksale kombiniert werden, aus denen diese Neuroblasten hervorgehen, wie z. B. ihre spezifischen neuronalen und glialen Schicksale.
... The exceptions include a subset of type I neuroblasts in the VNC that switch to type 0 and terminally differentiate into postmitotic neural cells [71,72]. In contrast, mushroom body neuroblasts and a pair of lateral neuroblasts in the CB do not become quiescent but keep proliferating throughout the embryonic-larval transition [68,73]. During early larval development, quiescent neuroblasts are reactivated in which they re-enter the cell cycle, increase in size and lose the primary basal protrusion [67,68,70,74]. ...
The formation of a functional circuitry in the central nervous system (CNS) requires the correct number and subtypes of neural cells. In the developing brain, neural stem cells (NSCs) self-renew while giving rise to progenitors that in turn generate differentiated progeny. As such, the size and the diversity of cells that make up the functional CNS depend on the proliferative properties of NSCs. In the fruit fly Drosophila, where the process of neurogenesis has been extensively investigated, extrinsic factors such as the microenvironment of NSCs, nutrients, oxygen levels and systemic signals have been identified as regulators of NSC proliferation. Here, we review decades of work that explores how extrinsic signals non-autonomously regulate key NSC characteristics such as quiescence, proliferation and termination in the fly.
