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, Marina Mapelli

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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.

Original languageEnglish
Article number1025
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Culurgioni, S., Mari, S., Bonetti, P., Gallini, S., Bonetto, G., Brennich, M., Round, A., Nicassio, F., & Mapelli, M. (2018). Insc:LGN tetramers promote asymmetric divisions of mammary stem cells. Nature Communications, 9(1), [1025]. https://doi.org/10.1038/s41467-018-03343-4