Abstract
Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases. Force sensing is one of the mechanisms through which division orientation is determined. Here we show that integrin β1 plays a critical role in this process, becoming activated at the lateral regions of the cell cortex in a ligand-independent manner. This activation is force dependent and polar, correlating with the spindle capture sites. Inhibition of integrin β1 activation on the cortex and disruption of its asymmetric distribution leads to spindle misorientation, even when cell adhesion is β1 independent. Examining downstream targets reveals that a cortical mechanosensory complex forms on active β1, and regulates spindle orientation irrespective of cell context. We propose that ligand-independent integrin β1 activation is a conserved mechanism that allows cell responses to external stimuli.
Highlights
Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases
Recent work from our group begun to unravel the molecular machinery responsible for force sensing in mitotic cells, when we showed that focal adhesion kinase (FAK)-null cells fail to orient their spindle in response to mechanical cues despite forming normal RFs5
We show that integrin b1 becomes asymmetrically activated at the lateral cortex of mitotic cells and that both the activation and the asymmetric distribution of active b1 are critical for correct spindle orientation
Summary
Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases. Cells seeded on PLL displayed spindle misorientation and lack of cortical b1 activation, confirming that activation of b1 on the lateral cortex during mitosis depends on RFs12 (Supplementary Fig. 3b–d).
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