Tapon lab Apoptosis and Proliferation Control Laboratory
: Differential proliferation rates generate patterns of mechanical tension that orient tissue growth
Introduction
Orientation of cell divisions is a key mechanism of tissue morphogenesis. In the growing Drosophila wing imaginal disc epithelium, most of the cell divisions in the central wing pouch are oriented along the proximal-distal (P-D) axis by the Ds-Ft-Dachs planar polarity pathway.
Stills from a movie of a laser ablation used to visualise differential tensions experienced by cell junctions in Drosophila larval wing epithelial cells. The arrowhead in A indicates the ablated junction. The frames in A. and B. show the cell junction before and after the cut, respectively. C. is a merge of A. and B.
However, cells at the periphery of the wing pouch instead tend to orient their divisions perpendicular to the P-D axis despite strong Dachs polarisation. In collaboration with Barry Thompson ( Epithelial Biology Group), Alexander Tournier (Mathematical Modelling Group) and Andreas Hoppe (Kingston University, London), we have shown that these circumferential divisions are oriented by circumferential mechanical forces (as measured by laser ablation experiments - Figure 1) that influence cell shapes and thus orient the mitotic spindle.
We propose that this circumferential pattern of force is not generated locally by polarised constriction of individual epithelial cells. Instead, these forces emerge as a global tension pattern that appears to originate from differential rates of cell proliferation within the wing pouch.
Accordingly, we show that localised overgrowth is sufficient to induce neighbouring cell stretching and reorientation of cell division. Our results suggest that patterned rates of cell proliferation can influence tissue mechanics and thus determine the orientation of cell divisions and tissue shape.
Recent theoretical work has suggested that mechanical feedback control of proliferation is a likely mediator of terminal proliferation arrest during wing disc development.
In particular, the pattern of compression in the centre and stretching in the periphery has been proposed to account for equilibrating the differences in pro-growth signals between the centre of the pouch (distal), where cells are exposed to high levels of the Dpp and Wg morphogens versus the periphery (proximal) where cells are exposed to lower morphogen levels. Yki (YAP in mammals) has been reported to respond to a cell's mechanical environment and might function as a growth-regulatory sensor of these physical inputs. While this is an attractive hypothesis, it was unclear how the patterns of stretch and compression observed in late discs arise in the first place.
Our data suggest that early differences in proliferation rates in the centre versus the periphery likely account for these patterns, which might feed back to increase proliferation in stretched outer cells, leading to proliferation rate equilibration. It will be interesting in the future to explore whether differential growth rates can influence the spatial pattern of Yki activation in vivo.
