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A sheath of motile cells supports collective migration in of the Zebrafish posterior lateral line primordium under the skin

Damian Dalle Nogare, Naveen Natesh, Ajay Chitnis

Preprint posted on 1 October 2019 https://www.biorxiv.org/content/10.1101/783043v2

Article now published in eLife at http://dx.doi.org/10.7554/elife.58251

More than just a barrier – the skin interacts with the posterior lateral line primordium in zebrafish to ensure collective cell migration

Selected by Karen Groß

Categories: developmental biology

Background

During embryogenesis tissues must work together to ensure proper development. Direct cellular signalling, tissue patterning and cell migration through complex 3D environments are crucial processes in development. The posterior lateral line (PLL) has been widely used as a model to study different aspects of these processes in vivo [1-3]. The zebrafish PLL is a sensory system that is generated by a cluster of collectively migrating cells, called PLL primordium. The PLL primordium migrates from the otic vesicle to the tail just under the skin depositing epithelial clusters, which form sensory organs, on its way along the horizontal myoseptum. Primordium migration depends on chemokine [4] and Fgf [5] signalling. Although the signals that guide the primordium along the tail are known, it is not entirely clear how the surrounding tissues and the primordium interact to ensure proper migration. In this preprint the authors find that specialized primordium cells on the apical side of the PLL primordium are in close contact with the overlying skin and extend directional migratory processes that are dependent on FGF signalling (similar to basal lamellipodia). Loss of this interaction by mechanical removal of the skin leads to stalling of the PLL primordium, suggesting that the interaction of primordium and surrounding tissues (both basally and apically) is crucial for primordium migration.

 

Key findings

PLL primordium cells are in direct contact with the skin and form highly polarized lamellipodia

To characterize the morphology of cells within the primordium the authors did a mosaic analysis of transplanted cells and uncovered a so far unrecognized cell type on the apical side of the primordium that form a sheath of cells covering the primordium (Figure 1). These cells are in direct contact with the overlying skin. Time-lapse and high-resolution imaging revealed that these cells are characterized by highly polarized lamellipodia that are formed mostly in the direction of migration. Moreover, retrograde actin flow suggests that the lamellipodia are used for active migration. This phenomenon has previously been described for cells on the basal side of the primordium and has been associated to the migratory behaviour of the primordium.

Figure 1: 3D reconstruction of the PLL primordium with apical cells in purple forming a sheath. Adapted from Nogare et al., 2019, figure 2G.

Lamellipodia polarization depends on Fgf signalling

The orientation of lamellipodia on cells on the basal side of the PLL primordium depends on Fgf signalling [5]. In order to test, whether apical lamellipodia depend on Fgf signalling as well, fish were treated with the Fgf inhibitor SU5402. And indeed, upon Fgf inhibition a loss of apical lamellipodia polarization was observed.

Primordium-skin interaction is crucial for apical and basal lamellipodia formation and migratory activity

Since there is extensive direct contact between the apical “sheath” cells and the overlying skin the authors wondered about the role of the skin during PLL primordium migration. To examine this the skin was mechanically removed. This led to stalling of the primordium, suggesting that direct contact with the skin is indispensable for primordium migration. Looking closely at the apical “sheath” cells, the authors realized that there was a drastic decrease in polarized lamellipodia. Surprisingly, not only apical cells, but also basal cell lamellipodia were affected by removal of the skin and showed the same phenotype of polarization loss, suggesting that not direct cell contact but the presence of a confining environment is necessary for lamellipodia polarization and migration. Both lamellipodia polarization and primordium migration were restored after regrowth of the skin.

 

Why I like this preprint

Apart from amazing microscopy images, the authors show how PLL primordium migration depends on the presence of another tissue, the overlying skin. Removal of the skin leads to failure of migration and further formation of the lateral line. This is a beautiful example for how tissues interact during development to ensure proper organogenesis.

 

Questions

Mechanical removal of the skin leads to stalling of the primordium. Does a similar phenotype occur after loss of lamellipodia polarization upon inhibition of Fgf signalling?

There are apical and basal cells covering the primordium that support collective migration of the primordium. However, to generate organs proneuromasts have to be deposited in certain intervals, meaning they have to stop migrating along with the primordium. Can they do so, because the apical and basal cells are not covering them anymore? And if yes, what regulates the position of the apical and basal cells?

 

References

  1. Chitnis, A.B., D.D. Nogare, and M. Matsuda, Building the posterior lateral line system in zebrafish. Dev Neurobiol, 2012. 72(3): p. 234-55.
  2. Ghysen, A. and C. Dambly-Chaudiere, The lateral line microcosmos. Genes Dev, 2007. 21(17): p. 2118-30.
  3. Friedl, P. and D. Gilmour, Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol, 2009. 10(7): p. 445-57.
  4. Haas, P. and D. Gilmour, Chemokine signaling mediates self-organizing tissue migration in the zebrafish lateral line. Dev Cell, 2006. 10(5): p. 673-80.
  5. Lecaudey, V., et al., Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium. Development, 2008. 135(16): p. 2695-705.

Tags: collective cell migration, lateral line, zebrafish

Posted on: 10 November 2019

doi: https://doi.org/10.1242/prelights.15115

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Author's response

Damian Dalle Nogare shared

  1. Mechanical removal of the skin leads to stalling of the primordium.Does a similar phenotype occur after loss of lamellipodia polarization upon inhibition of Fgf signalling?

Yes, a failure of migration upon FGF inhibition, associated with loss of polarization of basal cryptic lamellipodia had been previously described by Darren Gilmour’s group. In fact, this is what prompted us to initially look at polarization of the apical lamellipodia after skin fgf inhibition and skin removal. The failure of apical protrusion polarization upon FGF inhibition (which correlated with failure of migration) was one of the first clues that we had that these processes might be acting as part of the migratory apparatus of this group of cells.

 

  1. There are apical and basal cells covering the primordium that support collective migration of the primordium. However, to generate organs proneuromasts have to be deposited in certain intervals, meaning they have to stop migrating along with the primordium. Can they do so, because the apical and basal cells are not covering them anymore? And if yes, what regulates the position of the apical and basal cells?

Your second question is one that we’ve thought a lot about, because the mechanisms that time deposition of neuromasts in this system are not very well understood. We’ve long been interested in what regulates the deposition of neuromasts – what, in effect, causes them to lose the ability to migrate and deposit. When we documented the decrease in apical cells around the trailing most neuromast (ie the one which was preparing to deposit), our initial thought was that loss of these cells might have something to do with why the trailing neuromast loses the ability to migrate and is deposited. However, this is at this point still just a correlation. It might be that the loss of these cells is an effect, rather than a cause, of neuromast deposition. Without knowing more about what regulates the activity and/or position of these cells, we couldn’t design an experiment to specifically interfere with them, either in a positive or negative way. This is something that we’re working on figuring out now, along with trying to find specific markers for this population.

 

Stepping back a little bit, this whole story started out when Naveen, who was a summer student in our lab, first tried to remove the primordium from under the skin so that we could transfer it to a dish. In the course of these experiments we noticed that removal of the skin prevented the primordium from moving completely. On the one hand, we were disappointed that our initial – apparently naive – thought of easily removing the primordium and placing it in a dish where we could study its migration in a controlled environment wasn’t going to pan out. On the other hand, letting Naveen instead spend the rest of his summer following up on this strange observation, which at the time we couldn’t explain, turned out to be quite fruitful, and led to the story that we have today.

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