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Abstract
SummaryProliferating animal cells are able to orient their mitotic spindles along their interphase cell axis, setting up the axis of cell division, despite rounding up as they enter mitosis. This has previously been attributed to molecular memory and, more specifically, to the maintenance of adhesions and retraction fibers in mitosis [1, 2, 3, 4, 5, 6], which are thought to act as local cues that pattern cortical Gαi, LGN, and nuclear mitotic apparatus protein (NuMA) [3, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. This cortical machinery then recruits and activates Dynein motors, which pull on astral microtubules to position the mitotic spindle. Here, we reveal a dynamic two-way crosstalk between the spindle and cortical motor complexes that depends on a Ran-guanosine triphosphate (GTP) signal [12], which is sufficient to drive continuous monopolar spindle motion independently of adhesive cues in flattened human cells in culture. Building on previous work [1, 12, 19, 20, 21, 22, 23], we implemented a physical model of the system that recapitulates the observed spindle-cortex interactions. Strikingly, when this model was used to study spindle dynamics in cells entering mitosis, the chromatin-based signal was found to preferentially clear force generators from the short cell axis, so that cortical motors pulling on astral microtubules align bipolar spindles with the interphase long cell axis, without requiring a fixed cue or a physical memory of interphase shape. Thus, our analysis shows that the ability of chromatin to pattern the cortex during the process of mitotic rounding is sufficient to translate interphase shape into a cortical pattern that can be read by the spindle, which then guides the axis of cell division.
Highlights
As spindles moved across the basal cell cortex, centrosomes led, tilted downward (Figures 1C–1E), while kinetochore-microtubules and DNA followed (Figures 1B and 1D)
We were able to use this simplified system to test whether cell-extracellular matrix (ECM) adhesions function as positional cues to guide spindle movements, as previously proposed [1]
In a rare flat, untreated cell in which a bipolar spindle broke into two, LGN was seen locally clearing from the basal membrane in the vicinity of both half-spindles (Figure S2F; Video S1C), implying that the effect is mediated by local short-range signaling. These data support the idea that LGN and other cortical proteins controlling Dynein-mediated forces on astral microtubules, together with the Ran-guanosine triphosphate (GTP) gradient centered on mitotic chromatin, constitute a dynamic feedback system that links the spindle and the cortex
Summary
As spindles moved across the basal cell cortex, centrosomes led, tilted downward (Figures 1C–1E), while kinetochore-microtubules and DNA followed (Figures 1B and 1D). The pattern of GFP-LGN accumulation in these experiments was both dynamic and closely correlated with monopolar spindle movement imaged by using a-tubulin-mCherry (Figures 2A and 2B; Video S1B).
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