Asymmetric cell division

Résumé

An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to symmetric cell divisions which give rise to daughter cells of equivalent fates. Notably, stem cells divide asymmetrically to give rise to two distinct daughter cells: one copy of the original stem cell as well as a second daughter programmed to differentiate into a non-stem cell fate. (In times of growth or regeneration, stem cells can also divide symmetrically, to produce two identical copies of the original cell.) In principle, there are two mechanisms by which distinct properties may be conferred on the daughters of a dividing cell. In one, the daughter cells are initially equivalent but a difference is induced by signaling between the cells, from surrounding cells, or from the precursor cell. This mechanism is known as extrinsic asymmetric cell division. In the second mechanism, the prospective daughter cells are inherently different at the time of division of the mother

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https://en.wikipedia.org/wiki/Asymmetric_cell_division

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Students will learn essentials of cell and developmental biology, with an emphasis on animal model systems and quantitative approaches.

Students are lead to understand selected concepts in cell and developmental biology, primarily through the analysis of scientific literature, and then to apply these concepts to the design and execution of a group project in the Gönczy or Oates laboratory.

Ce cours présente les principes fondamentaux à l'œuvre dans les organismes vivants. Autant que possible, l'accent est mis sur les contributions de l'Informatique aux progrès des Sciences de la Vie.

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Asymmetric cell division is essential for the generation of diversity during development and the function of stem cell lineages. The Caenorhabditis elegans zygote is an attractive model to investigate the mechanisms of spindle positioning during asymmetric cell division. In this polarized cell, the asymmetric distribution of cortical force generators along the antero-posterior axis and pulling on astral microtubules leads to the unequal cleavage of the one-cell embryo. The mechanisms underlying such cortical force generation are thought to act strictly at the protein level. In this thesis work we report that the mRNA encoding the cortical force generator component LIN-5 is enriched around centrosomes in early embryos, in a manner that depends on microtubules and dynein. We established that the lin-5 coding sequence is necessary and sufficient for mRNA enrichment around centrosomes in C. elegans. In addition, we found that lin-5 mRNA is mislocalized in lin-5(ev571) mutant embryos, which harbor a 9 nucleotide insertion in the coding sequence. Moreover, an intragenic revertant of lin-5(ev571), lin-5(ev571he63), also exhibits mislocalized lin-5 mRNA distribution. We demonstrated that this is accompanied by diminished pulling forces on the posterior spindle pole, suggesting that centrosomal localization of lin-5 mRNA is important for robust pulling forces. We found also that lin-5 mRNA centrosomal enrichment is slightly asymmetric during anaphase, with more transcripts present on the anterior side. We developed a novel FRAP-based assay, which revealed that lin-5 is translated/folded preferentially in the cytoplasm compared to centrosomes. Furthermore, we found that morpholino-mediated inhibition of lin-5 translation diminishes pulling forces on the posterior side during anaphase. Together, these findings lead us to propose that preferential translation/folding of lin-5 in the posterior cytoplasm following release of the mRNA from the posterior centrosome contributes to asymmetric cortical distribution of force generators, and thus to proper spindle positioning. Moreover, we found that the mRNA of an uncharacterized gene, era-1 is enriched on the anterior side of the zygote and is inherited by the anterior blastomeres. Similar to era-1 mRNA, a YFP fusion of ERA-1 protein is also asymmetrically distributed. Moreover, asymmetric distribution of both era-1 mRNA and YFP-ERA-1 protein requires the era-1 3'UTR. Furthermore, the RNA-binding protein MEX-5 is needed for both asymmetric era-1 mRNA localization and for its translational activation. Furthermore, we report that the clathrin heavy chain CHC-1 negatively regulates pulling forces acting on centrosomes during interphase and on spindle poles during mitosis in one-cell C. elegans embryos. We establish a similar role for the cytokinesis/apoptosis/RNA-binding protein CAR-1 and uncover that CAR-1 is needed to maintain normal levels of CHC-1. We demonstrate that CHC-1 is necessary for proper organization of the cortical acto-myosin network and for full cortical tension. Furthermore, we establish that the centrosome positioning phenotype of embryos depleted of CHC-1 is alleviated by stabilizing the acto-myosin network. Conversely, we demonstrate that slight perturbations of the acto-myosin network results in excess centrosome movements. Overall, our findings lead us to propose that clathrin plays a critical role in centrosome positioning by promoting acto-myosin cortical tension.

EPFL2014

Chargement

Characterization of RGS-7 as a regulator of forces involved in C. elegans early cell divisions

Simon Germann

Proper regulation of cell division is crucial to most organisms. Asymmetric division and unequal cleavage are one of the many mechanisms by which spatial regulation of cell division might be achieved. Indeed, by varying its polarity cues or by modulating the size of its daughters, a cell can potentially influence its cellular neighborhood and possibly act upon it. In C. elegans, asymmetric cell division occurs at early stages of development, and is induced by an asymmetric positioning of the spindle during mitosis. RGS-7, a member of the RGS protein family, is a potential candidate as a regulator of this process, and was shown to affect the balance of pulling forces responsible for the asymmetric position of the spindle, possibly acting through Gα and/or Gβ, which are heterotrimeric G-protein complex subunits involved in force generation in C. elegans early cell divisions. However, many aspects of the role this protein may have in this process remain to be elucidated. Using available rgs-7 mutants, RNA interference, spindle severing experiments and immunofluorescence assays, this study highlights the potential functions RGS-7 may provide to a dividing C. elegans embryo

2008

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Asymmetric Spindle Positioning and Intracellular Trafficking in C. Elegans Embryos

Kalyani Thyagarajan

Asymmetric cell division is critical for generating daughter cells that possess distinct fates during development and in stem cell lineages. Correct orientation of the mitotic spindle with respect to the polarity axis is crucial to this process. In the one-cell stage embryo of the nematode C. elegans, polarity cues define an anterior-posterior axis, and the mitotic spindle is positioned asymmetrically towards the posterior of the embryo in response to these cues, resulting in daughter cells that differ not only in fates, but also in sizes. Although the way by which force is generated has becoming increasingly well understood, the mechanisms by which polarity cues regulate the asymmetric distribution of active cortical force generators that pull on astral microtubules to position the spindle remained unclear at the onset of my thesis. During the course of our work, we found that intracellular trafficking plays a crucial role in the distribution and levels of proteins involved in asymmetric spindle positioning. Firstly, we found that the distribution of the Gβ protein GPB-1, a negative regulator of pulling forces, varies across the cell cycle, with levels at the cell membrane being lowest during mitosis. GPB-1 transits through the endosomal network in a dynamin-, clathrin- and RAB-5-dependent manner. We also found that GPB-1 trafficking is more pronounced on the anterior side and that this asymmetry is regulated by A-P polarity cues. In addition, we demonstrate that GPB-1 depletion results in the loss of GPR-1/2 asymmetry during mitosis, and thus symmetric pulling forces during mitosis. Secondly, we found that the clathrin heavy chain modulates spindle-positioning forces as well as the cortical distribution of positive (GPR-1/2 and DHC-1) and negative (GPB-1 and LET-99) regulators of pulling forces. Although the mechanisms by which it does so remain unclear, our data suggests that clathrin plays multiple roles in the one-cell stage C. elegans embryos, including in recycling GPB-1 to the plasma membrane. Overall, our results lead us to propose that the clathrin heavy chain and the modulation of Gβγ trafficking play a critical role during asymmetric division of one-cell stage C. elegans embryos.

EPFL2011

Chargement

EPFL2014

Asymmetric Spindle Positioning and Intracellular Trafficking in C. Elegans Embryos

Kalyani Thyagarajan

EPFL2011