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¹ KAN Research Institute, Inc., 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan
² Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute 480-1195, Aichi, Japan
³ Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine/Faculty of Medicine, Kobe 650-0017, Hyogo, Japan
⁴ Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Osaka, Japan

Orientation of mitotic spindle and cell division axis can impact normal physiological processes, including epithelial tissue branching and neuron generation by asymmetric cell division. Microtubule dynamics and its interaction with cortical proteins regulate the orientation of mitotic spindle axis. However, the nature of extracellular signals that control proper orientation of mitotic spindle axis is largely unclear. Here, we show that signals from two distinct surface contact, "bi-surface-contact," sites are required for the orientation of mitotic spindle axis in normal epithelial cells. We identified apical and basal surface-membrane as required bi-surface-contact sites. We showed that high molecular weight (HMW) hyaluronan (HA)–CD44 signaling from the apical surface-membrane regulated the orientation of mitotic spindle axis to align parallel to the basal extracellular matrix (ECM). The same effect was achieved by fibronectin–integrin vβ6 signaling from the basal surface-membrane or by inhibition of ROCK activity. On the contrary, HMW HA–CD44 signaling from the basal surface-membrane regulated the orientation of mitotic spindle axis to align oblique-perpendicular to the basal ECM. We also found that microtubule dynamics is required for HMW HA–CD44 mediated regulation of mitotic spindle orientation. Our findings thus provide a novel mechanism for the regulation of mitotic spindle orientation.

^* Correspondence: Email: t-fujiwara{at}kan.eisai.co.jp