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

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.

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

Development ◽

10.1242/dev.191544 ◽

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.

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

Journal of Developmental Biology ◽

10.3390/jdb6040025 ◽

2018 ◽

Vol 6 (4) ◽

pp. 25 ◽

Cited By ~ 7

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.

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Phase Separation and Mechanical Forces in Regulating Asymmetric Cell Division of Neural Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms221910267 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10267

Author(s):

Yiqing Zhang ◽

Heyang Wei ◽

Wenyu Wen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Phase Separation ◽

Cell Division ◽

Neural Stem Cells ◽

Asymmetric Cell Division ◽

Stem Cell Population ◽

Mechanical Forces ◽

Major Mechanism ◽

Asymmetrically Distributed

Asymmetric cell division (ACD) of neural stem cells and progenitors not only renews the stem cell population but also ensures the normal development of the nervous system, producing various types of neurons with different shapes and functions in the brain. One major mechanism to achieve ACD is the asymmetric localization and uneven segregation of intracellular proteins and organelles into sibling cells. Recent studies have demonstrated that liquid-liquid phase separation (LLPS) provides a potential mechanism for the formation of membrane-less biomolecular condensates that are asymmetrically distributed on limited membrane regions. Moreover, mechanical forces have emerged as pivotal regulators of asymmetric neural stem cell division by generating sibling cell size asymmetry. In this review, we will summarize recent discoveries of ACD mechanisms driven by LLPS and mechanical forces.

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Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽

10.1182/blood.2020009778 ◽

2021 ◽

Author(s):

Dirk Loeffler ◽

Florin Schneiter ◽

Weijia Wang ◽

Arne Wehling ◽

Tobias Kull ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Division ◽

Cell Fate ◽

Human Blood ◽

Asymmetric Cell Division ◽

Cell Fates ◽

Hematopoietic Stem ◽

Stem Cell Fate ◽

Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

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Maintenance of Pluripotent Stem Cells is Influenced by Ser/Thr Metabolism

Blood ◽

10.1182/blood.v124.21.sci-43.sci-43 ◽

2014 ◽

Vol 124 (21) ◽

pp. SCI-43-SCI-43

Author(s):

Lewis C. Cantley

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Embryonic Stem ◽

Isocitrate Dehydrogenase 1 ◽

Advisory Committees ◽

Metabolic Intermediates ◽

Stem Cell Maintenance ◽

Differentiated Cells ◽

Methylation Of Dna

Abstract Recent studies have suggested not only that stem cells have different metabolic requirements than terminally differentiated cells, but also that metabolic intermediates may play a role in the maintenance of stem cells. It has long been clear that changes in acetylation and methylation of histones, as well as methylation of DNA play critical roles in deciding cell fate. The availability of critical intermediates in metabolism, especially S-adenosylmethionine (SAM), acetyl-CoA, nicotinamide adenine dinucleotide (NAD) and a-ketoglutarate play critical roles in modulating acetylation and methylation of histones and methylation of DNA. In the course of evaluating an unusual requirement of threonine (Thr) for the growth of murine embryonic stem cells, we found that metabolism of Thr to glycine (Gly) and the subsequent use of the methyl group of Gly for converting homocysteine to methionine is critical for maintaining high levels of SAM and low levels of S-adenosyl-homocysteine. Importantly, depletion of Thr from the media resulted in decreased tri-methylation of histone H3 lysine-4 (H3K4me3), leading to slowed growth and increased differentiation. Thus, abundance of SAM appears to influence H3K4me3, providing a possible mechanism by which modulation of a metabolic pathway might influence stem cell fate. Demethylation of histones and DNA can also be controlled by metabolic intermediates. Mutated forms of isocitrate dehydrogenase 1 (IDH1) and IDH2 that drive acute myeloid leukemia (AML) and other cancers, produce an oncometabolite (2-hydrogyglutarate) that can compete with the a-ketoglutarate requirement for enzymes involved in hydroxy-methylation and subsequent demethylation of DNA and histones. Recent studies indicate that 2-hydroxyglutarate plays a role in blocking differentiation of cancer cells. These and other observations linking intermediates in metabolism to stem cell maintenance will be discussed. Disclosures Cantley: Agios Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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Mathematical modeling of plant cell fate transitions controlled by hormonal signals

10.1101/830190 ◽

2019 ◽

Author(s):

Filip Z. Klawe ◽

Thomas Stiehl ◽

Peter Bastian ◽

Christophe Gaillochet ◽

Jan U. Lohmann ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Stem Cell ◽

Transcription Factors ◽

Cell Division ◽

Cell Fate ◽

Plant Architecture ◽

Two Dimensional ◽

Cell Dynamics ◽

Non Linear

AbstractCoordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to elucidate the impact of hormonal signaling on the fate transition rates between different zones corresponding to slowly dividing stem cells and fast dividing transit amplifying cells. The model is based on a simplified two-dimensional disc geometry of the SAM and accounts for a continuous displacement towards the periphery of cells produced in the central zone. Coupling growth and hormonal signaling results in a non-linear system of reaction-diffusion equations on a growing domain with the growth velocity depending on the model components. The model is tested by simulating perturbations in the level of key transcription factors that maintain SAM homeostasis. The model provides new insights on how the transcription factor HECATE is integrated in the regulatory network that governs stem cell differentiation.SummaryPlants continuously generate new organs such as leaves, roots and flowers. This process is driven by stem cells which are located in specialized regions, so-called meristems. Dividing stem cells give rise to offspring that, during a process referred to as cell fate transition, become more specialized and give rise to organs. Plant architecture and crop yield crucially depend on the regulation of meristem dynamics. To better understand this regulation, we develop a computational model of the shoot meristem. The model describes the meristem as a two-dimensional disk that can grow and shrink over time, depending on the concentrations of the signalling factors in its interior. This allows studying how the non-linear interaction of multiple transcription factors is linked to cell division and fate-transition. We test the model by simulating perturbations of meristem signals and comparing them to experimental data. The model allows simulating different hypotheses about signal effects. Based on the model we study the specific role of the transcription factor HECATE and provide new insights in its action on cell dynamics and in its interrelation with other known transcription factors in the meristem.

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

The Journal of Cell Biology ◽

10.1083/jcb.201711167 ◽

2018 ◽

Vol 217 (9) ◽

pp. 3285-3300 ◽

Cited By ~ 12

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.

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Coordinate control of basal epithelial cell fate and stem cell maintenance by core EMT transcription factor Zeb1

Cell Reports ◽

10.1016/j.celrep.2021.110240 ◽

2022 ◽

Vol 38 (2) ◽

pp. 110240

Author(s):

Yingying Han ◽

Alvaro Villarreal-Ponce ◽

Guadalupe Gutierrez ◽

Quy Nguyen ◽

Peng Sun ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Epithelial Cell ◽

Cell Fate ◽

Stem Cell Maintenance ◽

Basal Epithelial Cell ◽

Coordinate Control ◽

Cell Maintenance

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The Expression Profiles of lncRNAs and Their Regulatory Network During Smek1/2 Knockout Mouse Neural Stem Cells Differentiation

Current Bioinformatics ◽

10.2174/1574893614666190308160507 ◽

2020 ◽

Vol 15 (1) ◽

pp. 77-88 ◽

Cited By ~ 1

Author(s):

Qichang Yang ◽

Jing Wu ◽

Jian Zhao ◽

Tianyi Xu ◽

Ping Han ◽

...

Keyword(s):

Stem Cells ◽

Nervous System ◽

Neural Stem Cells ◽

Cell Fate ◽

Expression Profiles ◽

Enrichment Analysis ◽

Differentially Expressed ◽

Wildtype Mouse ◽

Pathway Network ◽

Differentiation And Proliferation

Background: Previous studies indicated that the cell fate of neural stem cells (NSCs) after differentiation is determined by Smek1, one isoform of suppressor of Mek null (Smek). Smek deficiency prevents NSCs from differentiation, thus affects the development of nervous system. In recent years, lncRNAs have been found to participate in numerous developmental and biological pathways. However, the effects of knocking out Smek on the expression profiles of lncRNAs during the differentiation remain unknown. Objective: This study is to explore the expression profiles of lncRNAs and their possible function during the differentiation from Smek1/2 knockout NSCs. Methods: We obtained NSCs from the C57BL/6J mouse fetal cerebral cortex. One group of NSCs was from wildtype mouse (WT group), while another group was from knocked out Smek1/2 (KO group). Results: By analyzing the RNA-Seq data, we found that after knocking out Smek1/2, the expression profiles of mRNAs and lncRNAs revealed significant changes. Analyses indicated that these affected mRNAs have connections with the pathway network for the differentiation and proliferation of NSCs. Furthermore, we performed a co-expression network analysis on the differentially expressed mRNAs and lncRNAs, which helped reveal the possible regulatory rules of lncRNAs during the differentiation after knocking out Smek1/2. Conclusion: By comparing group WT with KO, we found 366 differentially expressed mRNAs and 12 lncRNAs. GO and KEGG enrichment analysis on these mRNAs suggested their relationships with differentiation and proliferation of NSCs. Some of these mRNAs and lncRNAs have been verified to play regulatory roles in nervous system. Analyses on the co-expression network also indicated the possible functions of affected mRNAs and lncRNAs during NSCs differentiation after knocking out Smek1/2.

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