Wnt Signaling and a Hox Protein Cooperatively Regulate PSA-3/Meis to Determine Daughter Cell Fate after Asymmetric Cell Division in C. elegans

PAR proteins (partitioning defective) are major regulators of cell polarity and asymmetric cell division. One of the par genes, par-1, encodes a Ser/Thr kinase that is conserved from yeast to mammals. In Caenorhabditis elegans, par-1 governs asymmetric cell division by ensuring the polar distribution of cell fate determinants. However the precise mechanisms by which PAR-1 regulates asymmetric cell division in C. elegans remain to be elucidated. We performed a genomewide RNAi screen and identified six genes that specifically suppress the embryonic lethal phenotype associated with mutations in par-1. One of these suppressors is mpk-1, the C. elegans homolog of the conserved mitogen activated protein (MAP) kinase ERK. Loss of function of mpk-1 restored embryonic viability, asynchronous cell divisions, the asymmetric distribution of cell fate specification markers, and the distribution of PAR-1 protein in par-1 mutant embryos, indicating that this genetic interaction is functionally relevant for embryonic development. Furthermore, disrupting the function of other components of the MAPK signaling pathway resulted in suppression of par-1 embryonic lethality. Our data therefore indicates that MAP kinase signaling antagonizes PAR-1 signaling during early C. elegans embryonic polarization.

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PLK-1 Regulation of Asymmetric Cell Division in the Early C. elegans Embryo

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.632253 ◽

2021 ◽

Vol 8 ◽

Author(s):

Amelia J. Kim ◽

Erik E. Griffin

Keyword(s):

Cell Division ◽

Cell Fate ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Asymmetric Cell Division ◽

Critical Role ◽

Cell Cortex ◽

C Elegans ◽

Mitotic Kinase ◽

Centrosome Separation

PLK1 is a conserved mitotic kinase that is essential for the entry into and progression through mitosis. In addition to its canonical mitotic functions, recent studies have characterized a critical role for PLK-1 in regulating the polarization and asymmetric division of the one-cell C. elegans embryo. Prior to cell division, PLK-1 regulates both the polarization of the PAR proteins at the cell cortex and the segregation of cell fate determinants in the cytoplasm. Following cell division, PLK-1 is preferentially inherited to one daughter cell where it acts to regulate the timing of centrosome separation and cell division. PLK1 also regulates cell polarity in asymmetrically dividing Drosophila neuroblasts and during mammalian planar cell polarity, suggesting it may act broadly to connect cell polarity and cell cycle mechanisms.

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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.

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Dynein dynamics at the microtubule plus-ends and cortex during division in the C. elegans zygote

10.1101/118604 ◽

2017 ◽

Cited By ~ 1

Author(s):

Ruddi Rodriguez-Garcia ◽

Laurent Chesneau ◽

Sylvain Pastezeur ◽

Julien Roul ◽

Marc Tramier ◽

...

Keyword(s):

Cell Division ◽

Daughter Cell ◽

Asymmetric Cell Division ◽

Budding Yeast ◽

Mitotic Progression ◽

Cell Fates ◽

C Elegans ◽

Detachment Rate ◽

Cortical Localization

AbstractDuring asymmetric cell division, dynein generates forces, which position the spindle to reflect polarity and ensure correct daughter cell fates. The transient cortical localization of dynein raises the question of its targeting. We found that it accumulates at the microtubule plus-ends like in budding yeast, indirectly hitch-hiking on EBP-2EB1 likely via dynactin. Importantly, this mechanism, which modestly accounts for cortical forces, does not transport dynein, which displays the same binding/unbinding dynamics as EBP-2EB1. At the cortex, dynein tracks can be classified as having either directed or diffusive-like motion. Diffusive-like tracks reveal force-generating dyneins. Their densities are higher on the posterior tip of the embryos, where GPR-1/2LGN concentrate, but their durations are symmetric. Since dynein flows to the cortex are non-polarized, we suggest that this posterior enrichment increases dynein binding, thus accounts for the force imbalance reflecting polarity, and supplements the regulation of mitotic progression via the non-polarized detachment rate.

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Centromere assembly and non-random sister chromatid segregation in stem cells

Essays in Biochemistry ◽

10.1042/ebc20190066 ◽

2020 ◽

Vol 64 (2) ◽

pp. 223-232 ◽

Cited By ~ 1

Author(s):

Ben L. Carty ◽

Elaine M. Dunleavy

Keyword(s):

Stem Cells ◽

Cell Division ◽

Cell Fate ◽

Sister Chromatid ◽

Asymmetric Cell Division ◽

Protein A ◽

Germline Stem Cells ◽

Sister Chromatids ◽

Centromere Protein A ◽

Oocyte Meiosis

Abstract Asymmetric cell division (ACD) produces daughter cells with separate distinct cell fates and is critical for the development and regulation of multicellular organisms. Epigenetic mechanisms are key players in cell fate determination. Centromeres, epigenetically specified loci defined by the presence of the histone H3-variant, centromere protein A (CENP-A), are essential for chromosome segregation at cell division. ACDs in stem cells and in oocyte meiosis have been proposed to be reliant on centromere integrity for the regulation of the non-random segregation of chromosomes. It has recently been shown that CENP-A is asymmetrically distributed between the centromeres of sister chromatids in male and female Drosophila germline stem cells (GSCs), with more CENP-A on sister chromatids to be segregated to the GSC. This imbalance in centromere strength correlates with the temporal and asymmetric assembly of the mitotic spindle and potentially orientates the cell to allow for biased sister chromatid retention in stem cells. In this essay, we discuss the recent evidence for asymmetric sister centromeres in stem cells. Thereafter, we discuss mechanistic avenues to establish this sister centromere asymmetry and how it ultimately might influence cell fate.

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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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Strontium regulates stem cell fate during osteogenic differentiation through asymmetric cell division

Acta Biomaterialia ◽

10.1016/j.actbio.2020.10.030 ◽

2021 ◽

Vol 119 ◽

pp. 432-443

Author(s):

Yanqun Li ◽

Jianhui Yue ◽

Yuan Liu ◽

Jun Wu ◽

Min Guan ◽

...

Keyword(s):

Stem Cell ◽

Cell Division ◽

Osteogenic Differentiation ◽

Cell Fate ◽

Asymmetric Cell Division ◽

Stem Cell Fate

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Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division

eLife ◽

10.7554/elife.33685 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Cuie Chen ◽

Ryan Cummings ◽

Aghapi Mordovanakis ◽

Alan J Hunt ◽

Michael Mayer ◽

...

Keyword(s):

Stem Cells ◽

Cell Division ◽

Cell Fate ◽

Cell Polarity ◽

Adult Stem Cells ◽

Asymmetric Cell Division ◽

Cytokine Receptor ◽

Spindle Orientation ◽

Germline Stem Cells ◽

Self Renewal

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

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