JAM-A regulates cortical dynein localization through Cdc42 to control planar spindle orientation during mitosis.

ABSTRACT

Planar spindle orientation in polarized epithelial cells depends on the precise localization of the dynein-dynactin motor protein complex at the lateral cortex. The contribution of cell adhesion molecules to the cortical localization of the dynein-dynactin complex is poorly understood. Here we find that junctional adhesion molecule-A (JAM-A) regulates the planar orientation of the mitotic spindle during epithelial morphogenesis. During mitosis, JAM-A triggers a transient activation of Cdc42 and PI(3)K, generates a gradient of PtdIns(3,4,5)P3 at the cortex and regulates the formation of the cortical actin cytoskeleton. In the absence of functional JAM-A, dynactin localization at the cortex is reduced, the mitotic spindle apparatus is misaligned and epithelial morphogenesis in three-dimensional culture is compromised. Our findings indicate that a PI(3)K- and cortical F-actin-dependent pathway of planar spindle orientation operates in polarized epithelial cells to regulate epithelial morphogenesis, and we identify JAM-A as a junctional regulator of this pathway.