Insc:LGN tetramers promote asymmetric divisions of mammary stem cells

Simone Culurgioni (), Sara Mari, Paola Bonetti, Sara Gallini, Greta Bonetto, Martha Brennich, Adam Round, Francesco Nicassio and Marina Mapelli ()
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Simone Culurgioni: European Institute of Oncology
Sara Mari: European Institute of Oncology
Paola Bonetti: Istituto Italiano di Tecnologia (IIT)
Sara Gallini: European Institute of Oncology
Greta Bonetto: European Institute of Oncology
Martha Brennich: Grenoble Outstation
Adam Round: Grenoble Outstation
Francesco Nicassio: Istituto Italiano di Tecnologia (IIT)
Marina Mapelli: European Institute of Oncology

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Asymmetric cell divisions balance stem cell proliferation and differentiation to sustain tissue morphogenesis and homeostasis. During asymmetric divisions, fate determinants and niche contacts segregate unequally between daughters, but little is known on how this is achieved mechanistically. In Drosophila neuroblasts and murine mammary stem cells, the association of the spindle orientation protein LGN with the stem cell adaptor Inscuteable has been connected to asymmetry. Here we report the crystal structure of Drosophila LGN in complex with the asymmetric domain of Inscuteable, which reveals a tetrameric arrangement of intertwined molecules. We show that Insc:LGN tetramers constitute stable cores of Par3–Insc-LGN-GαiGDP complexes, which cannot be dissociated by NuMA. In mammary stem cells, the asymmetric domain of Insc bound to LGN:GαiGDP suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. We suggest a novel role for the Insc-bound pool of LGN acting independently of microtubule motors to promote asymmetric fate specification.

Date: 2018
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DOI: 10.1038/s41467-018-03343-4

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