Epithelial tricellular junctions act as interphase cell shape sensors to orient mitosis

Abstract

The orientation of cell division along the interphase cell long-axis, the century old Hertwig’s rule, has profound roles in tissue proliferation, morphogenesis, architecture and mechanics1,2. In epithelial tissues, the shape of the interphase cell is influenced by cell adhesion, mechanical stress, neighbour topology, and planar polarity pathways3–12. At mitosis, epithelial cells usually round up to ensure faithful chromosome segregation and to promote morphogenesis1. The mechanisms underlying interphase cell shape sensing in tissues are therefore unknown. We found that in Drosophila epithelia, tricellular junctions (TCJ) localize microtubule force generators, orienting cell division via the Dynein associated protein Mud independently of the classical Pins/Gαi pathway. Moreover, as cells round up during mitosis, TCJs serve as spatial landmarks, encoding information about interphase cell shape anisotropy to orient division in the rounded mitotic cell. Finally, experimental and simulation data show that shape and mechanical strain sensing by the TCJ emerge from a general geometric property of TCJ distributions in epithelial tissues. Thus, in addition to their function as epithelial barrier structures, TCJs serve as polarity cues promoting geometry and mechanical sensing in epithelial tissues.

Spindle orientation: a question of complex positioning

“…Although these findings suggest that spindle orientation in the A-B axis is inessential, additional work in the fruit fly shows that spindle orientation can help to determine the direction of tissue expansion, which is governed by mechanical tension across the tissue (BaenaLópez et al, 2005;Bosveld et al, 2016;Mao et al, 2011). This is consistent with earlier work implicating spindle orientation in determining the shape of epithelial tubes in the lung (Tang et al, 2011).…”

“…Intriguingly, these results suggest that vertebrate and insect epithelia use different systems for localizing the spindle-orientation machinery, as spindles are not oriented by adherens junctions in Drosophila (Bergstralh et al, 2013;Bosveld et al, 2016).…”

Collective migration and cell jamming in asthma, cancer and development

“…In that connection, Hertwig's rule holds that cell division tends to orient along the long axis of the interphase cell (Hertwig, 1893), and this propensity has been argued to facilitate both stress relaxation and isotropic growth with no need for cells to transduce local mechanical signals (Wyatt et al, 2015). Nevertheless, the tricellular junctions in Drosophila epithelium serve as a polarity cue for geometry and mechanical stress that acts through the dynein-associated protein Mud (Bosveld et al, 2016). Although our emphasis here is on events within the epithelial cell layer plane, it is important to recognize that not all pertinent epithelial events are necessarily restricted to lie within that plane.…”

Automated cell tracking identifies mechanically oriented cell divisions during Drosophila axis elongation

“…Par-3 regulates cell division orientation by recruiting the G-protein regulator Pins (Schober et al, 1999;Wodarz et al, 1999;Yu et al, 2000;Schaefer et al, 2001) and the Pins-binding protein Mud (Bowman et al, 2006;Izumi et al, 2006;Siller et al, 2006), which form a complex that interacts with the microtubule-based motor Dynein and facilitates spindle orientation (Merdes et al, 1996). Recent data show that in the dorsal thorax of the Drosophila pupa, Mud localizes to tricellular junctions independently of Pins and regulates the pulling forces that astral microtubules exert on centrosomes (Bosveld et al, 2016). Thus, the distribution of tricellular junctions around a dividing cell determines centrosome position, spindle alignment and cell division orientation.…”

“…Mechanical forces can orient cell division in developing animals (Le Goff and Lecuit, 2011;Mao et al, 2011;Campinho et al, 2013;Mao et al, 2013;Bosveld et al, 2016). In the Drosophila embryo, defects in AP patterning disrupt cell division orientation on the posterior germband (da Silva and Vincent, 2007).…”