Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria

Susanna Eli, Greta Rauso, Paola Ghezzi, James L. A. Szczerkowski, Michela Bruzzi, Francesca Rizzelli, Fabiola Iommazzo, Alessia Loffreda, Francesco Castagna, Federico Donà, Chiara Gaddoni, Ambra Dondi, Mattia Marenda, Simona Rodighiero, Pierre Tournier, Zeno Lavagnino, Dario Parazzoli, Nils C. Gauthier, Simone Tamburri, Diego Pasini, Shukry James Habib () and Marina Mapelli ()
Additional contact information
Susanna Eli: European Institute of Oncology IRCCS, IEO
Greta Rauso: European Institute of Oncology IRCCS, IEO
Paola Ghezzi: European Institute of Oncology IRCCS, IEO
James L. A. Szczerkowski: University of Lausanne, Department of Biomedical Sciences
Michela Bruzzi: European Institute of Oncology IRCCS, IEO
Francesca Rizzelli: European Institute of Oncology IRCCS, IEO
Fabiola Iommazzo: European Institute of Oncology IRCCS, IEO
Alessia Loffreda: Experimental Imaging Center, IRCCS Ospedale San Raffaele
Francesco Castagna: European Institute of Oncology IRCCS, IEO
Federico Donà: European Institute of Oncology IRCCS, IEO
Chiara Gaddoni: European Institute of Oncology IRCCS, IEO
Ambra Dondi: European Institute of Oncology IRCCS, IEO
Mattia Marenda: European Institute of Oncology IRCCS, IEO
Simona Rodighiero: European Institute of Oncology IRCCS, IEO
Pierre Tournier: University of Lausanne, Department of Biomedical Sciences
Zeno Lavagnino: The AIRC Institute of Molecular Oncology, IFOM ETS
Dario Parazzoli: The AIRC Institute of Molecular Oncology, IFOM ETS
Nils C. Gauthier: The AIRC Institute of Molecular Oncology, IFOM ETS
Simone Tamburri: European Institute of Oncology IRCCS, IEO
Diego Pasini: European Institute of Oncology IRCCS, IEO
Shukry James Habib: University of Lausanne, Department of Biomedical Sciences
Marina Mapelli: European Institute of Oncology IRCCS, IEO

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract In multicellular organisms, the execution of developmental and homeostatic programs often relies on asymmetric cell divisions. These divisions require the alignment of the mitotic spindle axis to cortical polarity cues, and the unequal partitioning of cellular components between progeny cells. Asymmetric divisions are orchestrated by signals from the niche frequently presented in a directional manner, such as Wnt signals. Here we employ bioengineered Wnt-niches to demonstrate that in metaphase NuMA/dynein microtubule motors form a complex with activated LRP6 and β-catenin at the cortical sites of Wnt activation to orient cell division perpendicularly. We show that engagement of LRP6 co-receptors by Wnt ligands locally stabilizes actomyosin contractility through the accumulation of myosin1C. Additionally, we describe a proteomic-based approach to identify mitotic protein complexes enriched at the Wnt-contact site, revealing that mitochondria polarize toward localized Wnt3a sources and are asymmetrically apportioned to the Wnt-proximal daughter cell during Wnt-mediated asymmetric cell division of embryonic stem cells. Mechanistically, we show that CENP-F is required for mitochondria polarization towards localized sites of Wnt3a activation, and that deletion of the Wnt-co-receptor LRP6 impairs the asymmetric apportioning of mitochondria. Our findings enhance the understanding of mitotic Wnt-signaling and elucidate fundamental principles underlying Wnt-dependent mitochondrial polarization.

Date: 2025
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DOI: 10.1038/s41467-025-65775-z

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