Proper control of division orientation and symmetry, largely determined by spindle positioning, is essential to development and homeostasis. Spindle positioning has been extensively studied in cells dividing in 2-dimensional (2D) environments and in epithelial tissues, where proteins such as NuMA orient division along the cell's interphase long axis. However, little is known about how cells control spindle positioning in 3-dimensional (3D) environments, such as early mammalian embryos and a variety of adult tissues. Here, we use mouse embryonic stem (ES) cells, which grow in 3D colonies, as a model to investigate division in 3D. We observe that at the periphery of 3D colonies, ES cells display high spindle mobility and divide asymmetrically. Our data suggest that enhanced spindle movements are due to unequal distribution of the cell-cell junction protein E-Cadherin between future daughter cells. Interestingly, when cells progress towards differentiation, division becomes more symmetric, with more elongated shapes in metaphase and enhanced cortical NuMA recruitment in anaphase. Altogether, this study suggests that in 3D contexts, the geometry of the cell and its contacts with neighbors control division orientation and symmetry.

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