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Cell lineage-dependent chiral actomyosin flows drive cellular rearrangements in early development

Lokesh Pimpale, Teije C. Middelkoop, Alexander Mietke, Stephan W. Grill

Preprint posted on November 14, 2019 https://www.biorxiv.org/content/10.1101/842922v1

Pimpale et al. show how chirality of cortical flows influences cell positioning throughout development.

Selected by Lars Hubatsch

How cells are positioned within tissues and developing organisms is a fundamental question in developmental biology. For example, during early C. elegans development, proper cell positioning is crucial for lineage establishment, which depends on cell-cell signaling between the correct sets of neighbors.

Proper positioning after division can be achieved by changing spindle orientation and thus the axis of division. Previous work by the Grill lab (Naganathan et al. 2014) suggested that chiral counter-rotation of the actomyosin cortex prior to division plays a role for division orientation during ABa and ABp cell divisions (also see fig 1a). However, the generality of this mechanism, molecular key players and much of the underlying physics remain unclear.

Here, in highly quantitative and thorough work, Pimpale et al. show for the first time that chiral counter-rotation causes repositioning of cells after division throughout the AB lineage. Contrarily, cells in the P/EMS lineage divide without counter-rotation and no spindle skew (see fig. 2b), giving rise to germline and endo/ectoderm. The authors show a causal relationship between counter-rotation and spindle skew by altering chiral flow velocities by RNAi and by disrupting chirality with a temperature sensitive nmy-2 mutant. Thus, chiral cortical flows drive spindle skew and are therefore responsible for proper cell positioning after division in the AB lineage.

Interestingly, a coarse-grain theoretical description of the cortex as a 2D active fluid, in which torque density is proportional to measured myosin intensity, can account quantitatively for the chiral flows in the AB lineage. Much of this theory is hidden in the supplement. In particular the supplementary discussion of how the myosin pattern across a cell (and therefore cell polarity) determines the type of flow seen in a specific cell makes for an interesting read. This part also starts to elucidate one of the most interesting future questions: What conveys the difference between counter-rotation in the AB lineage and net rotation of the cell in the P lineage?


Questions to the authors:

The theory assumes uniform friction while the discussion makes explicit mention of the necessity of non-uniform friction. Can you comment on this apparent discrepancy?

To answer this, it is important to distinguish the properties of friction with surrounding material that affect (i) cortical flow profiles measured essentially within a thin strip of cortex along the long axis of the embryo (these are fitted by the theory) and (ii) global asymmetries in the friction that the whole cortical surface experiences (as mentioned in discussion and Fig. 2f). The latter type of friction is not appearing in the theory, but is an indispensable ingredient of the mechanism that counter-rotating flows on the surface lead to reorientations of the overall cell. In the case of a globally inhomogeneous friction, shown as a minimal scenario in Fig. 2f, torques that are transferred to the boundary don’t cancel each other out. The remaining difference leads to a rotation and reorientation of the cell itself. Independently of this, the assumption of a homogeneous friction for the theory (case (i)) to discuss the occurrence of the different flow types (‘counter-rotating’ and ‘net-rotating’) was chosen as a simplification. From the good quantitative agreement between the theory and the observed flows (Supplement Fig. 3a and 3b), we conclude that such inhomogeneities do not play an important role in AB-lineage divisions.

Is it asymmetry or absolute levels of anterior/posterior polarity determinants that determine the type of flows? What happens in overexpression mutants when anterior cells inherit more pPARs but still divide symmetrically (e.g. codon-optimized PAR-2/PAR-6 lines, partial rundowns of aPARs/pPARs)?

The asymmetric distribution of polarity determinants determines asymmetry of anterior/posterior myosin concentration and cytokinetic ring location. We show that these two parameters determine the type of flow. Assuming that parpolarity acts upstream of RhoA signaling, we suspect that absolute levels of polarity determinants would influence the concentration of myosin, affecting only the chiral counter-rotating flow velocity (similar to perturbing RhoA signaling in Fig. 3). This is not in conflict with such a cell still dividing symmetrically. 

Have you tried other mutants that disrupt the coupling between the actomyosin cortex and the mitotic spindle to further show what’s important for the skew of the division axis?

That’s a very nice question! Yes, we did try a few RNAi conditions namely lin-5(RNAi) or gpr-2(RNAi) to disrupt coupling between the actomyosin cortex and the mitotic spindle. We observed reduced counter-rotating flow velocities in these conditions that correlate with reduced rates of spindle skew for the AB cell. However, incoherent movements of the spindle of the AB and of the P1 cell as well as the altered cell division axis of the P1 cell induced by RNAi make the data highly variable and difficult to interpret. In a wild-type cell, the mitotic spindle is essential and required for formation of cytokinetic ring at its position. Our work suggests that chiral actomyosin flows mechanically drive and act upstream to cellular repositioning during cytokinesis.

 

Posted on: 4th December 2019

doi: https://doi.org/10.1242/prelights.15562

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