SAPCD2 Controls Spindle Orientation and Asymmetric Divisions by Negatively Regulating the Gαi-LGN-NuMA Ternary Complex

Dev Cell. 2016 Jan 11;36(1):50-62. doi: 10.1016/j.devcel.2015.12.016.

Catherine W N Chiu ¹, Carine Monat ², Mélanie Robitaille ¹, Marine Lacomme ³, Avais M Daulat ¹, Graham Macleod ¹, Helen McNeill ⁴, Michel Cayouette ⁵, Stéphane Angers ⁶

Affiliations

1 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada.
2 Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada; Department of Medicine, Université de Montréal, QC H3T 1J4, Canada.
3 Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada.
4 Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
5 Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada; Department of Medicine, Université de Montréal, QC H3T 1J4, Canada; Department of Anatomy and Cell Biology and Division of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada. Electronic address: [email protected].
6 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, University of Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].

PMID: 26766442 DOI: 10.1016/j.devcel.2015.12.016

Abstract

Control of cell-division orientation is integral to epithelial morphogenesis and asymmetric cell division. Proper spatiotemporal localization of the evolutionarily conserved Gαi-LGN-NuMA protein complex is critical for mitotic spindle orientation, but how this is achieved remains unclear. Here we identify Suppressor APC domain containing 2 (SAPCD2) as a previously unreported LGN-interacting protein. We show that SAPCD2 is essential to instruct planar mitotic spindle orientation in both epithelial cell cultures and mouse retinal progenitor cells in vivo. Loss of SAPCD2 randomizes spindle orientation, which in turn disrupts cyst morphogenesis in three-dimensional cultures, and triples the number of terminal asymmetric cell divisions in the developing retina. Mechanistically, we show that SAPCD2 negatively regulates the localization of LGN at the cell cortex, likely by competing with NuMA for its binding. These results uncover SAPCD2 as a key regulator of the ternary complex controlling spindle orientation during morphogenesis and asymmetric cell divisions.

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