C. elegans Runx/CBFβ suppresses POP-1(TCF) to convert asymmetric to proliferative division of stem cell-like seam cells

ABSTRACTA correct balance between proliferative and asymmetric cell divisions underlies normal development, stem cell maintenance and tissue homeostasis. What determines whether cells undergo symmetric or asymmetric cell division is poorly understood. To gain insight in the mechanisms involved, we studied the stem cell-like seam cells in the Caenorhabditis elegans epidermis. Seam cells go through a reproducible pattern of asymmetric divisions, instructed by non-canonical Wnt/β-catenin asymmetry signaling, and symmetric divisions that increase the seam cell number. Using time-lapse fluorescence microscopy, we show that symmetric cell divisions maintain the asymmetric localization of Wnt/β-catenin pathway components. Observations based on lineage-specific knockout and GFP-tagging of endogenous pop-1 support the model that POP-1TCF induces differentiation at a high nuclear level, while low nuclear POP-1 promotes seam cell self-renewal. Before symmetric division, the transcriptional regulator rnt-1Runx and cofactor bro-1CBFβ temporarily bypass Wnt/β-catenin asymmetry by downregulating pop-1 expression. Thereby, RNT-1/BRO-1 appears to render POP-1 below the level required for its repressor function, which converts differentiation into self-renewal. Thus, opposition between the C. elegans Runx/CBFβ and TCF stem-cell regulators controls the switch between asymmetric and symmetric seam cell division.

Download Full-text

Mafb Restricts M-CSF Instructed Lineage Choice in HSC

Blood ◽

10.1182/blood.v116.21.sci-15.sci-15 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-15-SCI-15

Author(s):

Michael H. Sieweke

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Cell Division ◽

Daughter Cell ◽

Critical Role ◽

Lineage Commitment ◽

Cytokine Signaling ◽

Self Renewal ◽

Cell Divisions ◽

Asymmetric Divisions

Abstract Abstract SCI-15 HSC need to enter the cycle to continuously regenerate mature blood cells in a correctly balanced ratio or to replenish the stem cell pool under stress conditions. Cell division of HSC may thus result in self-renewal divisions or the production of more differentiated progeny. Although such downstream progenitors still retain a high degree of multi-potency, recent advances in their characterization also suggest that early diversification into cells with distinct lineage bias can occur at the most primitive stem and precursor cell level. Whereas multiple cellular regulators have been identified that affect self-renewal of HSC, regulators that selectively control lineage specific commitment divisions of HSC are only beginning to be elucidated. Both transcription factor and cytokine signaling may play important roles in lineage engagement but it has been a long-standing debate, whether cytokine signaling has instructive or permissive effects on lineage commitment. In this context we reported that deficiency for the monocytic transcription factor MafB specifically sensitized HSC populations to M-CSF induced cell division and myeloid lineage commitment. We observed that MafB deficiency resulted in a specific up-regulation of the early myeloid transcription factor PU.1 and a dramatically enhanced myeloid specific repopulation activity that did not affect self-renewal or differentiation into other lineages. Our results point to a role for MafB in the maintenance of a balanced lineage potential of HSC by selectively restricting myeloid commitment divisions that give rise to PU.1+ progenitors in response to M-CSF signaling. Together this suggests that the potential of stem cells to produce differentiated progeny of a specific lineage bias can be subject to control by integrated cytokine/transcription factor circuits, where variation in cell intrinsic sensitivity limits like those set by MafB can render external cues such as M-CSF instructive. Stem cell self renewal or differentiation is associated with two different types of cell divisions, namely symmetric divisions that generate two identical daughter cells, or asymmetric divisions that produce a daughter cell with maintained stem cell properties and a daughter cell committed to a specific differentiation pathway. Our observation that reduced MafB levels specifically increased M-CSF stimulated asymmetric divisions giving rise to PU.1−/PU.1+ daughter pairs provides a conclusive explanation why increased myeloid commitment of MafB−/− HSC does not come at the expense of self-renewal or other lineages. The micro-environment can play a critical role in specifying the symmetry of cell divisions, but so far, investigations have focused on niche micro-environments that support HSC self-renewal. It is unknown whether environments also exist that support HSC commitment to specific lineages by enabling asymmetric divisions at the niche border. Using video-imaging approaches and genetic manipulation of the stem cell and stromal cell compartments we explore how cues from the microenvironment can affect asymmetric HSC division and lineage commitment. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

A role for the fusogen eff-1 in epidermal stem cell number robustness in Caenorhabditis elegans

Scientific Reports ◽

10.1038/s41598-021-88500-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sneha L. Koneru ◽

Fu Xiang Quah ◽

Ritobrata Ghose ◽

Mark Hintze ◽

Nicola Gritti ◽

...

Keyword(s):

Stem Cell ◽

Caenorhabditis Elegans ◽

Cell Fate ◽

Single Molecule ◽

Phenotypic Variability ◽

Low Frequency ◽

Time Lapse ◽

Cell Number ◽

Seam Cell ◽

Neuronal Tissues

AbstractDevelopmental patterning in Caenorhabditis elegans is known to proceed in a highly stereotypical manner, which raises the question of how developmental robustness is achieved despite the inevitable stochastic noise. We focus here on a population of epidermal cells, the seam cells, which show stem cell-like behaviour and divide symmetrically and asymmetrically over post-embryonic development to generate epidermal and neuronal tissues. We have conducted a mutagenesis screen to identify mutants that introduce phenotypic variability in the normally invariant seam cell population. We report here that a null mutation in the fusogen eff-1 increases seam cell number variability. Using time-lapse microscopy and single molecule fluorescence hybridisation, we find that seam cell division and differentiation patterns are mostly unperturbed in eff-1 mutants, indicating that cell fusion is uncoupled from the cell differentiation programme. Nevertheless, seam cell losses due to the inappropriate differentiation of both daughter cells following division, as well as seam cell gains through symmetric divisions towards the seam cell fate were observed at low frequency. We show that these stochastic errors likely arise through accumulation of defects interrupting the continuity of the seam and changing seam cell shape, highlighting the role of tissue homeostasis in suppressing phenotypic variability during development.

Download Full-text

Emerging mechanisms of asymmetric stem cell division

The Journal of Cell Biology ◽

10.1083/jcb.201807037 ◽

2018 ◽

Vol 217 (11) ◽

pp. 3785-3795 ◽

Cited By ~ 42

Author(s):

Zsolt G. Venkei ◽

Yukiko M. Yamashita

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Division ◽

Asymmetric Cell Division ◽

Binary Outcomes ◽

Cellular Mechanisms ◽

Asymmetric Cell Divisions ◽

Cell Divisions ◽

Dividing Cells ◽

Stem Cell Division

The asymmetric cell division of stem cells, which produces one stem cell and one differentiating cell, has emerged as a mechanism to balance stem cell self-renewal and differentiation. Elaborate cellular mechanisms that orchestrate the processes required for asymmetric cell divisions are often shared between stem cells and other asymmetrically dividing cells. During asymmetric cell division, cells must establish asymmetry/polarity, which is guided by varying degrees of intrinsic versus extrinsic cues, and use intracellular machineries to divide in a desired orientation in the context of the asymmetry/polarity. Recent studies have expanded our knowledge on the mechanisms of asymmetric cell divisions, revealing the previously unappreciated complexity in setting up the cellular and/or environmental asymmetry, ensuring binary outcomes of the fate determination. In this review, we summarize recent progress in understanding the mechanisms and regulations of asymmetric stem cell division.

Download Full-text

Roles of Actin in the Morphogenesis of the Early Caenorhabditis elegans Embryo

International Journal of Molecular Sciences ◽

10.3390/ijms21103652 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3652

Author(s):

Dureen Samandar Eweis ◽

Julie Plastino

Keyword(s):

Cell Division ◽

Caenorhabditis Elegans ◽

Asymmetric Cell Division ◽

Cell Types ◽

Actin Dynamics ◽

Actin Binding ◽

Asymmetric Cell Divisions ◽

C Elegans ◽

Asymmetric Divisions ◽

Different Cell Types

The cell shape changes that ensure asymmetric cell divisions are crucial for correct development, as asymmetric divisions allow for the formation of different cell types and therefore different tissues. The first division of the Caenorhabditis elegans embryo has emerged as a powerful model for understanding asymmetric cell division. The dynamics of microtubules, polarity proteins, and the actin cytoskeleton are all key for this process. In this review, we highlight studies from the last five years revealing new insights about the role of actin dynamics in the first asymmetric cell division of the early C. elegans embryo. Recent results concerning the roles of actin and actin binding proteins in symmetry breaking, cortical flows, cortical integrity, and cleavage furrow formation are described.

Download Full-text

Multiple levels of regulation specify the polarity of an asymmetric cell division in C. elegans

Development ◽

10.1242/dev.127.21.4587 ◽

2000 ◽

Vol 127 (21) ◽

pp. 4587-4598 ◽

Cited By ~ 3

Author(s):

J. Whangbo ◽

J. Harris ◽

C. Kenyon

Keyword(s):

Cell Division ◽

Wnt Signaling ◽

Epidermal Cell ◽

Asymmetric Cell Division ◽

Asymmetric Cell Divisions ◽

Signaling Systems ◽

Tissue Polarity ◽

C Elegans ◽

Cell Divisions ◽

A Cell

Wnt signaling systems play important roles in the generation of cell and tissue polarity during development. We describe a Wnt signaling system that acts in a new way to orient the polarity of an epidermal cell division in C. elegans. In this system, the EGL-20/Wnt signal acts in a permissive fashion to polarize the asymmetric division of a cell called V5. EGL-20 regulates this polarization by counteracting lateral signals from neighboring cells that would otherwise reverse the polarity of the V5 cell division. Our findings indicate that this lateral signaling pathway also involves Wnt pathway components. Overexpression of EGL-20 disrupts both the asymmetry and polarity of lateral epidermal cell divisions all along the anteroposterior (A/P) body axis. Together our findings suggest that multiple, inter-related Wnt signaling systems may act together to polarize asymmetric cell divisions in this tissue.

Download Full-text

Asymmetric cell division of mammary stem cells

Cell Division ◽

10.1186/s13008-021-00073-w ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Shaan N. Chhabra ◽

Brian W. Booth

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Stem Cell ◽

Cell Division ◽

Asymmetric Cell Division ◽

Mammary Stem Cells ◽

Self Renewal ◽

Symmetric Division ◽

Daughter Cells ◽

Mammary Stem

AbstractSomatic stem cells are distinguished by their capacity to regenerate themselves and also to produce daughter cells that will differentiate. Self-renewal is achieved through the process of asymmetric cell division which helps to sustain tissue morphogenesis as well as maintain homeostasis. Asymmetric cell division results in the development of two daughter cells with different fates after a single mitosis. Only one daughter cell maintains “stemness” while the other differentiates and achieves a non-stem cell fate. Stem cells also have the capacity to undergo symmetric division of cells that results in the development of two daughter cells which are identical. Symmetric division results in the expansion of the stem cell population. Imbalances and deregulations in these processes can result in diseases such as cancer. Adult mammary stem cells (MaSCs) are a group of cells that play a critical role in the expansion of the mammary gland during puberty and any subsequent pregnancies. Furthermore, given the relatively long lifespans and their capability to undergo self-renewal, adult stem cells have been suggested as ideal candidates for transformation events that lead to the development of cancer. With the possibility that MaSCs can act as the source cells for distinct breast cancer types; understanding their regulation is an important field of research. In this review, we discuss asymmetric cell division in breast/mammary stem cells and implications on further research. We focus on the background history of asymmetric cell division, asymmetric cell division monitoring techniques, identified molecular mechanisms of asymmetric stem cell division, and the role asymmetric cell division may play in breast cancer.

Download Full-text

Faculty Opinions recommendation of Intermittent Stem Cell Cycling Balances Self-Renewal and Senescence of the C. elegans Germ Line.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726286344.793529024 ◽

2017 ◽

Author(s):

Ilya Ruvinsky

Keyword(s):

Stem Cell ◽

Germ Line ◽

Self Renewal ◽

C Elegans ◽

Cell Cycling

Download Full-text

The role of lin-22, a hairy/enhancer of split homolog, in patterning the peripheral nervous system of C. elegans

Development ◽

10.1242/dev.124.15.2875 ◽

1997 ◽

Vol 124 (15) ◽

pp. 2875-2888 ◽

Cited By ~ 5

Author(s):

L.A. Wrischnik ◽

C.J. Kenyon

Keyword(s):

Stem Cell ◽

Regulatory Gene ◽

Epidermal Cells ◽

Body Axis ◽

Wild Type ◽

Hox Gene ◽

C Elegans ◽

Cell Divisions ◽

Body Regions ◽

Stem Cell Divisions

In C. elegans, six lateral epidermal stem cells, the seam cells V1-V6, are located in a row along the anterior-posterior (A/P) body axis. Anterior seam cells (V1-V4) undergo a fairly simple sequence of stem cell divisions and generate only epidermal cells. Posterior seam cells (V5 and V6) undergo a more complicated sequence of cell divisions that include additional rounds of stem cell proliferation and the production of neural as well as epidermal cells. In the wild type, activity of the gene lin-22 allows V1-V4 to generate their normal epidermal lineages rather than V5-like lineages. lin-22 activity is also required to prevent additional neurons from being produced by one branch of the V5 lineage. We find that the lin-22 gene exhibits homology to the Drosophila gene hairy, and that lin-22 activity represses neural development within the V5 lineage by blocking expression of the posterior-specific Hox gene mab-5 in specific cells. In addition, in order to prevent anterior V cells from generating V5-like lineages, wild-type lin-22 gene activity must inhibit (directly or indirectly) at least five downstream regulatory gene activities. In anterior body regions, lin-22(+) inhibits expression of the Hox gene mab-5. It also inhibits the activity of the achaete-scute homolog lin-32 and an unidentified gene that we postulate regulates stem cell division. Each of these three genes is required for the expression of a different piece of the ectopic V5-like lineages generated in lin-22 mutants. In addition, lin-22 activity prevents two other Hox genes, lin-39 and egl-5, from acquiring new activities within their normal domains of function along the A/P body axis. Some, but not all, of the patterning activities of lin-22 in C. elegans resemble those of hairy in Drosophila.

Download Full-text

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.

Download Full-text