A cytokinetic ring-driven cell rotation achieves Hertwig’s rule in early development

Abstract

AbstractCells tend to divide along the direction in which they are longest, as famously stated by Oscar Hertwig in 1884 in his ‘long axis’ rule1,2. The orientation of the mitotic spindle determines the cell division axis3, and Hertwig’s long axis rule is usually ensured by forces stemming from microtubules4. Pulling on the spindle from the cell cortex can give rise to unstable behaviors5,6, and we here set out to understand how Hertwig’s long axis rule is realized in early embryonic divisions where cortical pulling forces are prevalent. We focus on earlyC. elegansdevelopment, where we compressed embryos to reveal that cortical pulling forces favor an alignment of the spindle with the cell’s short axis. Strikingly, we find that this misalignment is corrected by an actomyosin-based mechanism that rotates the entire cell, including the mitotic spindle. We uncover that myosin-driven contractility in the cytokinetic ring generates inward forces that align it with the short axis, and thereby the spindle with the long axis. A theoretical model together with experiments using slightly compressed mouse zygotes suggest that a constricting cytokinetic ring can ensure Hertwig’s long axis rule in cells that are free to rotate inside a confining structure, thereby generalizing the underlying principle.