Mitotic spindle orientation and dynamics are fine-tuned by anisotropic tissue stretch via NuMA localisation

Cell division orientation, which is key to cell fate and shaping tissues, is influenced by mechanical forces. For example, in uniaxially stretched tissue most divisions orient along the stretch axis. This mechanosensitive division orientation can be achieved by distinct mechanisms involving a direct response to force or an indirect response to force via cell shape changes. Cells also generally align divisions along their long axis of interphase shape. Since stretching a tissue elongates cells, uncoupling whether divisions orient in response to force or to cell shape remains challenging. Here, we utilised the Xenopus laevis embryonic animal cap tissue and applied a reproducible external stretch to understand mechanosensitive division orientation. We focused on nuclear mitotic apparatus protein (NuMA), which is key to spindle orientation. We show that NuMA is dynamically localised to the cell cortex earlier during mitosis in uniaxially stretched tissues. This temporal cortical recruitment of NuMA coincides with the onset and subsequent stretch-induced amplification of spindle oscillations. Additionally, we show that knockdown of NuMA reduces spindle oscillations and disrupts division orientation according to stretch and cell shape. We also show that divisions dynamically align with cell shape under tissue stretch and this involves a direct response to force via NuMA localisation, rather than an indirect response to force via cell shape changes. Overall, using live tissue imaging, mathematical modelling, and tissue mechanics our results indicate that NuMA fine tunes spindle dynamics and ensures the accurate alignment of divisions with cell shape and anisotropic tension.