scholarly journals Cell biology of stem cells: an enigma of asymmetry and self-renewal

2008 ◽  
Vol 180 (2) ◽  
pp. 257-260 ◽  
Author(s):  
Haifan Lin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Cell Cycle Regulators ◽  
Germline Stem Cells ◽  
Central Question ◽  
Daughter Cells ◽  
Mammalian Skin ◽  
Asymmetric Divisions ◽  
Stem Cell Division

Stem cells present a vast, new terrain of cell biology. A central question in stem cell research is how stem cells achieve asymmetric divisions to replicate themselves while producing differentiated daughter cells. This hallmark of stem cells is manifested either strictly during each mitosis or loosely among several divisions. Current research has revealed the crucial roles of niche signaling, intrinsic cell polarity, subcellular localization mechanism, asymmetric centrosomes and spindles, as well as cell cycle regulators in establishing self-renewing asymmetry during stem cell division. Much of this progress has benefited from studies in model stem cell systems such as Drosophila melanogaster neuroblasts and germline stem cells and mammalian skin stem cells. Further investigations of these questions in diverse types of stem cells will significantly advance our knowledge of cell biology and allow us to effectively harness stem cells for therapeutic applications.

scholarly journals CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells

2020 ◽  
Author(s):  
Ben L Carty ◽  
Anna A Dattoli ◽  
Elaine M Dunleavy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Asymmetric Divisions ◽  
Centromere Assembly

AbstractGermline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies) - the epigenetic determinant of centromere identity - is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of ‘mitotic drive’ that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

scholarly journals CENP-C functions in centromere assembly, the maintenance of CENP-A asymmetry and epigenetic age in Drosophila germline stem cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (5) ◽  
pp. e1009247
Author(s):  
Ben L. Carty ◽  
Anna A. Dattoli ◽  
Elaine M. Dunleavy
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germ Line ◽  
Asymmetric Distribution ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Sister Chromatids ◽  
Asymmetric Divisions ◽  
Centromere Assembly

Germline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies)—the epigenetic determinant of centromere identity—is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of ‘mitotic drive’ that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

scholarly journals Mad dephosphorylation at the nuclear envelope is essential for asymmetric stem cell division

2019 ◽  
Author(s):  
Justin Sardi ◽  
Muhammed Burak Bener ◽  
Taylor Simao ◽  
Abigail E. Descoteaux ◽  
Boris M. Slepchenko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Short Range ◽  
Bmp Signaling ◽  
Nuclear Pore ◽  
Germline Stem Cells ◽  
Daughter Cells ◽  
Stem Cell Division ◽  
Cell Niche

SummaryStem cell niche signals act over a short range so that only stem cells but not the differentiating daughter cells receive the self-renewal signals. Drosophila female germline stem cells (GSCs) are maintained by short range BMP signaling; BMP ligands Dpp/Gbb activate receptor Tkv to phosphorylate Mad (phosphor-Mad or pMad) which accumulates in the GSC nucleus and activates the stem cell transcription program. pMad is highly concentrated in the nucleus of the GSC, but is immediately downregulated in the nucleus of the pre-cystoblast (preCB), a differentiating daughter cell, that is displaced away from the niche. Here we show that this asymmetry in the intensity of pMad is formed even before the completion of cytokinesis. A delay in establishing the pMad asymmetry leads to germline tumors through conversion of differentiating cells into a stem cell-like state. We show that a Mad phosphatase Dullard (Dd) interacts with Mad at the nuclear pore, where it may dephosphorylate Mad. A mathematical model explains how an asymmetry can be established in a common cytoplasm. It also demonstrates that the ratio of pMad concentrations in GSC/preCB is highly sensitive to Mad dephosphorylation rate. Our study reveals a previously unappreciated mechanism for breaking symmetry between daughter cells during asymmetric stem cell division.

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.

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 Mad dephosphorylation at the nuclear pore is essential for asymmetric stem cell division

2021 ◽  
Vol 118 (13) ◽  
pp. e2006786118
Author(s):  
Justin Sardi ◽  
Muhammed Burak Bener ◽  
Taylor Simao ◽  
Abigail E. Descoteaux ◽  
Boris M. Slepchenko ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Daughter Cell ◽  
High Sensitivity ◽  
Bmp Signaling ◽  
Nuclear Pore ◽  
Germline Stem Cells ◽  
Stem Cell Division ◽  
Asymmetric Partitioning

Stem cells divide asymmetrically to generate a stem cell and a differentiating daughter cell. Yet, it remains poorly understood how a stem cell and a differentiating daughter cell can receive distinct levels of niche signal and thus acquire different cell fates (self-renewal versus differentiation), despite being adjacent to each other and thus seemingly exposed to similar levels of niche signaling. In the Drosophila ovary, germline stem cells (GSCs) are maintained by short range bone morphogenetic protein (BMP) signaling; the BMP ligands activate a receptor that phosphorylates the downstream molecule mothers against decapentaplegic (Mad). Phosphorylated Mad (pMad) accumulates in the GSC nucleus and activates the stem cell transcription program. Here, we demonstrate that pMad is highly concentrated in the nucleus of the GSC, while it quickly decreases in the nucleus of the differentiating daughter cell, the precystoblast (preCB), before the completion of cytokinesis. We show that a known Mad phosphatase, Dullard (Dd), is required for the asymmetric partitioning of pMad. Our mathematical modeling recapitulates the high sensitivity of the ratio of pMad levels to the Mad phosphatase activity and explains how the asymmetry arises in a shared cytoplasm. Together, these studies reveal a mechanism for breaking the symmetry of daughter cells during asymmetric stem cell division.

scholarly journals Towards identifying subnetworks from FBF binding landscapes in Caenorhabditis spermatogenic or oogenic germlines

2018 ◽  
Author(s):  
Douglas F. Porter ◽  
Aman Prasad ◽  
Brian H. Carrick ◽  
Peggy Kroll-Connor ◽  
Marvin Wickens ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Cycle Regulators ◽  
Germline Stem Cells ◽  
Stem Cell Regulation ◽  
Cell Functions ◽  
Almost All

AbstractMetazoan PUF (Pumilio and FBF) RNA-binding proteins regulate various biological processes, but a common theme across phylogeny is stem cell regulation. In Caenorhabditis elegans, FBF (fem-3 Binding Factor) maintains germline stem cells regardless of which gamete is made, but FBF also functions in the process of spermatogenesis. We have begun to “disentangle” these biological roles by asking which FBF targets are gamete-independent, as expected for stem cells, and which are gamete-specific. Specifically, we compared FBF iCLIP binding profiles in adults making sperm to those making oocytes. Normally, XX adults make oocytes. To generate XX adults making sperm, we used a fem-3(gf) mutant requiring growth at 25°; for comparison, wild-type oogenic hermaphrodites were also raised at 25°. Our FBF iCLIP data revealed FBF binding sites in 1522 RNAs from oogenic adults and 1704 RNAs from spermatogenic adults. More than half of these FBF targets were independent of germline gender. We next clustered RNAs by FBF-RNA complex frequencies and found four distinct blocks. Block I RNAs were enriched in spermatogenic germlines, and included validated target fog-3, while Block II and III RNAs were common to both genders, and Block IV RNAs were enriched in oogenic germlines. Block II (510 RNAs) included almost all validated FBF targets and was enriched for cell cycle regulators. Block III (21 RNAs) was enriched for RNA-binding proteins, including previously validated FBF targets gld-1 and htp-1. We suggest that Block I RNAs belong to the FBF network for spermatogenesis, and that Blocks II and III are associated with stem cell functions.

scholarly journals Heparan sulfate regulates the number and centrosome positioning of Drosophila male germline stem cells

2016 ◽  
Vol 27 (6) ◽  
pp. 888-896 ◽  
Author(s):  
Daniel C. Levings ◽  
Takeshi Arashiro ◽  
Hiroshi Nakato
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Heparan Sulfate ◽  
Molecular Mechanisms ◽  
Asymmetric Division ◽  
Germline Stem Cells ◽  
Cell Behaviors ◽  
Male Germline ◽  
Drosophila Testis ◽  
Stem Cell Division

Stem cell division is tightly controlled via secreted signaling factors and cell adhesion molecules provided from local niche structures. Molecular mechanisms by which each niche component regulates stem cell behaviors remain to be elucidated. Here we show that heparan sulfate (HS), a class of glycosaminoglycan chains, regulates the number and asymmetric division of germline stem cells (GSCs) in the Drosophila testis. We found that GSC number is sensitive to the levels of 6- O sulfate groups on HS. Loss of 6- O sulfation also disrupted normal positioning of centrosomes, a process required for asymmetric division of GSCs. Blocking HS sulfation specifically in the niche, termed the hub, led to increased GSC numbers and mispositioning of centrosomes. The same treatment also perturbed the enrichment of Apc2, a component of the centrosome-anchoring machinery, at the hub–GSC interface. This perturbation of the centrosome-anchoring process ultimately led to an increase in the rate of spindle misorientation and symmetric GSC division. This study shows that specific HS modifications provide a novel regulatory mechanism for stem cell asymmetric division. The results also suggest that HS-mediated niche signaling acts upstream of GSC division orientation control.

scholarly journals Centrosome-dependent asymmetric inheritance of the midbody ring in Drosophila germline stem cell division

2014 ◽  
Vol 25 (2) ◽  
pp. 267-275 ◽  
Author(s):  
Viktoria Salzmann ◽  
Cuie Chen ◽  
C.-Y. Ason Chiang ◽  
Amita Tiyaboonchai ◽  
Michael Mayer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Germline Stem Cell ◽  
Dependent Manner ◽  
Germline Stem Cells ◽  
Cell Identity ◽  
Dividing Cells ◽  
Stem Cell Division ◽  
Functional Relevance

Many stem cells, including Drosophila germline stem cells (GSCs), divide asymmetrically, producing one stem cell and one differentiating daughter. Cytokinesis is often asymmetric, in that only one daughter cell inherits the midbody ring (MR) upon completion of abscission even in apparently symmetrically dividing cells. However, whether the asymmetry in cytokinesis correlates with cell fate or has functional relevance has been poorly explored. Here we show that the MR is asymmetrically segregated during GSC divisions in a centrosome age–dependent manner: male GSCs, which inherit the mother centrosome, exclude the MR, whereas female GSCs, which we here show inherit the daughter centrosome, inherit the MR. We further show that stem cell identity correlates with the mode of MR inheritance. Together our data suggest that the MR does not inherently dictate stem cell identity, although its stereotypical inheritance is under the control of stemness and potentially provides a platform for asymmetric segregation of certain factors.

Sign in / Sign up

Export Citation Format

Share Document