# Spindle Orientation Regulation Is Governed by Redundant Cortical Mechanosensing and Shape-Sensing Mechanisms

## TL;DR

Cells use two parallel mechanisms—shape sensing and force sensing—to regulate spindle orientation during division, ensuring adaptability in different environments.

## Contribution

The discovery of a dual, redundant system for spindle orientation regulation involving both shape and force sensing.

## Key findings

- The long prometaphase axis is a better predictor of spindle orientation than the long interphase axis.
- FAK-dependent force sensing aligns the spindle with the major force vector in cells undergoing complete metaphase rounding.
- A FAK-independent shape-sensing mechanism drives spindle orientation in cells with shape anisotropy during mitosis.

## Abstract

Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- and force-sensing mechanisms remains poorly understood. Here, we reveal that SO is governed by two parallel mechanisms that ensure redundancy and adaptability in diverse cellular environments. Using live-cell imaging of cultured cells, we demonstrate that the long prometaphase axis (LPA) is a superior predictor of SO compared to the long interphase axis, reflecting adhesive geometry and force distribution efficiently at prometaphase. Importantly, we uncover a pivotal role for focal adhesion kinase (FAK) in mediating cortical mechanosensing to regulate SO in cells undergoing complete metaphase rounding. We show that in cells with complete metaphase rounding, FAK-dependent force sensing aligns the spindle with the major force vector, ensuring accurate division. Conversely, in cells retaining shape anisotropy during mitosis, a FAK-independent shape-sensing mechanism drives SO. These findings highlight a dual regulatory system for SO, where shape sensing and force sensing operate in parallel to maintain division plane fidelity, shedding light on the mechanisms that enable cells to adapt to diverse physical and mechanical environments.