scholarly journals Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma

2018 ◽  
Vol 115 (31) ◽  
pp. E7351-E7360 ◽  
Author(s):  
Laura Kerosuo ◽  
Pushpa Neppala ◽  
Jenny Hsin ◽  
Sofie Mohlin ◽  
Felipe Monteleone Vieceli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Crest ◽  
Cell Fate ◽  
Poor Prognosis ◽  
Ectopic Expression ◽  
Mycn Amplification ◽  
Neural Crest Stem Cell ◽  
Enhanced Expression

Neuroblastoma is a neural crest-derived childhood tumor of the peripheral nervous system in which MycN amplification is a hallmark of poor prognosis. Here we show that MycN is expressed together with phosphorylation-stabilizing factor CIP2A in regions of the neural plate destined to form the CNS, but MycN is excluded from the neighboring neural crest stem cell domain. Interestingly, ectopic expression of MycN or CIP2A in the neural crest domain biases cells toward CNS-like neural stem cells that express Sox2. Consistent with this, some forms of neuroblastoma have been shown to share transcriptional resemblance with CNS neural stem cells. As high MycN/CIP2A levels correlate with poor prognosis, we posit that a MycN/CIP2A-mediated cell-fate bias may reflect a possible mechanism underlying early priming of some aggressive forms of neuroblastoma. In contrast to MycN, its paralogue cMyc is normally expressed in the neural crest stem cell domain and typically is associated with better overall survival in clinical neuroblastoma, perhaps reflecting a more “normal” neural crest-like state. These data suggest that priming for some forms of aggressive neuroblastoma may occur before neural crest emigration from the CNS and well before sympathoadrenal specification.

scholarly journals Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

2020 ◽  
Author(s):  
Srivathsa S. Magadi ◽  
Chrysanthi Voutyraki ◽  
Gerasimos Anagnostopoulos ◽  
Evanthia Zacharioudaki ◽  
Ioanna K. Poutakidou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Transcription Factor ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Transcriptional Networks ◽  
Malignant Tumours ◽  
Stem Cell Maintenance

ABSTRACTNeural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

scholarly journals Time-resolved transcriptomics in neural stem cells identifies a v-ATPase/Notch regulatory loop

2018 ◽  
Vol 217 (9) ◽  
pp. 3285-3300 ◽  
Author(s):  
Sebastian Wissel ◽  
Heike Harzer ◽  
François Bonnay ◽  
Thomas R. Burkard ◽  
Ralph A. Neumüller ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Cell Biology ◽  
Transcriptional Profiling ◽  
Nervous System Development ◽  
Time Resolved ◽  
Daughter Cells ◽  
Regulatory Loop

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 this study, we use time-resolved transcriptional profiling to identify the earliest transcriptional differences between the daughter cells on their way toward distinct fates. By screening for coregulated protein complexes, we identify vacuolar-type H+–ATPase (v-ATPase) among the first and most significantly down-regulated complexes in differentiating daughter cells. We show that v-ATPase is essential for NB growth and persistent activity of the Notch signaling pathway. Our data suggest that v-ATPase and Notch form a regulatory loop that acts in multiple stem cell lineages both during nervous system development and in the adult gut. We provide a unique resource for investigating neural stem cell biology and demonstrate that cell fate changes can be induced by transcriptional regulation of basic, cell-essential pathways.

Stem cell fate: extracellular glutamine shock for identification of key metabolic influencers in pluripotent and neural stem cells

2018 ◽  
Vol 44 ◽  
pp. S87
Author(s):  
J. Vasconcelos E Sá ◽  
D. Simão ◽  
M.M. Silva ◽  
A.P. Terrasso ◽  
I.A. Isidro ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Stem Cell Fate

scholarly journals Cytokinetic Abscission Regulation in Neural Stem Cells and Tissue Development

2021 ◽  
Author(s):  
Katrina C. McNeely ◽  
Noelle D. Dwyer
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Cell Polarity ◽  
Cell Biology ◽  
Tissue Growth ◽  
Developmentally Regulated ◽  
Daughter Cells ◽  
Fate Determinants

Abstract Purpose of Review How stem cells balance proliferation with differentiation, giving rise to specific daughter cells during development to build an embryo or tissue, remains an open question. Here, we discuss recent evidence that cytokinetic abscission regulation in stem cells, particularly neural stem cells (NSCs), is part of the answer. Abscission is a multi-step process mediated by the midbody, a microtubule-based structure formed in the intercellular bridge between daughter cells after mitosis. Recent Findings Human mutations and mouse knockouts in abscission genes reveal that subtle disruptions of NSC abscission can cause brain malformations. Experiments in several epithelial systems have shown that midbodies serve as scaffolds for apical junction proteins and are positioned near apical membrane fate determinants. Abscission timing is tightly controlled and developmentally regulated in stem cells, with delayed abscission in early embryos and faster abscission later. Midbody remnants (MBRs) contain over 400 proteins and may influence polarity, fate, and ciliogenesis. Summary As NSCs and other stem cells build tissues, they tightly regulate three aspects of abscission: midbody positioning, duration, and MBR handling. Midbody positioning and remnants establish or maintain cell polarity. MBRs are deposited on the apical membranes of epithelia, can be released or internalized by surrounding cells, and may sequester fate determinants or transfer information between cells. Work in cell lines and simpler systems has shown multiple roles for abscission regulation influencing stem cell polarity, potency, and daughter fates during development. Elucidating how the abscission process influences cell fate and tissue growth is important for our continued understanding of brain development and stem cell biology.

scholarly journals Plant stem-cell organization and differentiation at single-cell resolution

2020 ◽  
Vol 117 (52) ◽  
pp. 33689-33699
Author(s):  
James W. Satterlee ◽  
Josh Strable ◽  
Michael J. Scanlon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Single Cell ◽  
Cell Fate ◽  
Cell Function ◽  
Ectopic Expression ◽  
Cellular Level ◽  
Organizing Center ◽  
Cell Niche

Plants maintain populations of pluripotent stem cells in shoot apical meristems (SAMs), which continuously produce new aboveground organs. We used single-cell RNA sequencing (scRNA-seq) to achieve an unbiased characterization of the transcriptional landscape of the maize shoot stem-cell niche and its differentiating cellular descendants. Stem cells housed in the SAM tip are engaged in genome integrity maintenance and exhibit a low rate of cell division, consistent with their contributions to germline and somatic cell fates. Surprisingly, we find no evidence for a canonical stem-cell organizing center subtending these cells. In addition, trajectory inference was used to trace the gene expression changes that accompany cell differentiation, revealing that ectopic expression of KNOTTED1 (KN1) accelerates cell differentiation and promotes development of the sheathing maize leaf base. These single-cell transcriptomic analyses of the shoot apex yield insight into the processes of stem-cell function and cell-fate acquisition in the maize seedling and provide a valuable scaffold on which to better dissect the genetic control of plant shoot morphogenesis at the cellular level.

scholarly journals Neural Stem Cells inDrosophila: Molecular Genetic Mechanisms Underlying Normal Neural Proliferation and Abnormal Brain Tumor Formation

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Nidhi Saini ◽  
Heinrich Reichert
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Tumor Formation ◽  
Asymmetric Cell Divisions ◽  
Fate Determinants ◽  
Cell Fate Determinants

Neural stem cells inDrosophilaare currently one of the best model systems for understanding stem cell biology during normal development and during abnormal development of stem cell-derived brain tumors. InDrosophilabrain development, the proliferative activity of neural stem cells called neuroblasts gives rise to both the optic lobe and the central brain ganglia, and asymmetric cell divisions are key features of this proliferation. The molecular mechanisms that underlie the asymmetric cell divisions by which these neuroblasts self-renew and generate lineages of differentiating progeny have been studied extensively and involve two major protein complexes, the apical complex which maintains polarity and controls spindle orientation and the basal complex which is comprised of cell fate determinants and their adaptors that are segregated into the differentiating daughter cells during mitosis. Recent molecular genetic work has establishedDrosophilaneuroblasts as a model for neural stem cell-derived tumors in which perturbation of key molecular mechanisms that control neuroblast proliferation and the asymmetric segregation of cell fate determinants lead to brain tumor formation. Identification of novel candidate genes that control neuroblast self-renewal and differentiation as well as functional analysis of these genes in normal and tumorigenic conditions in a tissue-specific manner is now possible through genome-wide transgenic RNAi screens. These cellular and molecular findings inDrosophilaare likely to provide valuable genetic links for analyzing mammalian neural stem cells and tumor biology.

scholarly journals Drosophila as a Model for Developmental Biology: Stem Cell-Fate Decisions in the Developing Nervous System

2018 ◽  
Vol 6 (4) ◽  
pp. 25 ◽  
Author(s):  
Katherine Harding ◽  
Kristin White
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Cell Behavior ◽  
Stem Cell Fate ◽  
Cell Fate Decisions ◽  
Unique System ◽  
Developing Nervous System

Stem cells face a diversity of choices throughout their lives. At specific times, they may decide to initiate cell division, terminal differentiation, or apoptosis, or they may enter a quiescent non-proliferative state. Neural stem cells in the Drosophila central nervous system do all of these, at stereotypical times and anatomical positions during development. Distinct populations of neural stem cells offer a unique system to investigate the regulation of a particular stem cell behavior, while comparisons between populations can lead us to a broader understanding of stem cell identity. Drosophila is a well-described and genetically tractable model for studying fundamental stem cell behavior and the mechanisms that underlie cell-fate decisions. This review will focus on recent advances in our understanding of the factors that contribute to distinct stem cell-fate decisions within the context of the Drosophila nervous system.

scholarly journals Dissecting Hes-centred transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev191544
Author(s):  
Srivathsa S. Magadi ◽  
Chrysanthi Voutyraki ◽  
Gerasimos Anagnostopoulos ◽  
Evanthia Zacharioudaki ◽  
Ioanna K. Poutakidou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Transcription Factor ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Transcriptional Networks ◽  
Malignant Tumours ◽  
The Impact

ABSTRACTNeural stem cells divide during embryogenesis and juvenile life to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that, in every asymmetric cell division, progenitors send a Delta-Notch signal to their sibling stem cells. Here, we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. We describe the impact of two of these ‘anti-stemness’ factors, Zfh1 and Gcm, on Notch/Hes-triggered tumorigenesis.

Ectopic expression of the Drosophila Bam protein eliminates oogenic germline stem cells

Development ◽  
1997 ◽  
Vol 124 (18) ◽  
pp. 3651-3662 ◽  
Author(s):  
B. Ohlstein ◽  
D. McKearin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Germ Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Limiting Factor ◽  
Germline Stem Cells ◽  
Stem Cell Divisions

The Drosophila germ-cell lineage has emerged as a remarkable system for identifying genes required for changes in cell fate from stem cells into more specialized cells. Previous work indicates that bam expression is necessary for cystoblast differentiation; bam mutant germ cells fail to differentiate, but instead proliferate like stem cells. This paper reports that ectopic expression of bam is sufficient to extinguish stem cell divisions. Heat-induced bam+ expression specifically eliminated oogenic stem cells while somatic stem cell populations were not affected. Together with previous studies of the timing of bam mRNA and protein expression and the state of arrest in bam mutant cells, these data implicate Bam as a direct regulator of the switch from stem cell to cystoblast. Surprisingly, ectopic bam+ had no deleterious consequences for male germline cells suggesting that Bam may regulate somewhat different steps of germ-cell development in oogenesis and spermatogenesis. We discuss a model for how bam+ could direct differentiation based on our data (McKearin and Ohlstein, 1995) that Bam protein is essential to assemble part of the germ-cell-specific organelle, the fusome. We propose that fusome biogenesis is an obligate step for cystoblast cell fate and that Bam is the limiting factor for fusome maturation in female germ cells.

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