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Molecular basis of asymmetric cell division

Director

Marina Mapelli

Activities

We are interested in the molecular mechanisms governing asymmetric stem cell divisions, with emphasis on the role of the mitotic spindle orientation in determining daughter cells’ fate.
The proper execution of asymmetric divisions is crucial in generating tissue diversity during development, as well as for tissue homeostasis and regeneration in adult organisms. Consistently, an increasing body of literature supports the notion that certain human cancers arise from abnormalities in adult stem cells asymmetric divisions, able to alter cell fate and leading to over-proliferation (the so called cancer stem cell hypothesis). Indeed failures in asymmetric divisions cause abnormal proliferation during mammalian neurogenesis and skin development, and correlated with cancer progression (Santoro, EMBO Rep. 2016).

To make a cell division asymmetric, the orientation of the mitotic spindle has to be tightly coordinated to cellular polarity. This way, daughter cells are properly positioned within the tissue, inherit unequal sets of fate determinants and follow differential fates. This observation sets the stage for our studies, aimed at gaining insight into the functional and organisational principles of the molecular machines orchestrating asymmetric cell divisions. To address this biological problem, we use a combination of high-resolution X-ray crystallography, biochemical analyses on reconstituted protein complexes and stem cell biology. Using the detailed molecular information delivered by our structural studies, we formulate precise models of how intrinsic properties of individual protein promote asymmetric mitoses, that we challenge in living cells. An emerging concept in the cancer field is that cancer stem cells may be responsible for relapse and resistance to anticancer therapies. In this view, a clear molecular description of processes underlying asymmetric cell divisions will be instrumental in identifying new stem-cell specific drug targets for therapeutical intervention.

  • Research projects

    Our activity is organized in three main research lines:


    1. Characterisation of molecular machines coordinating asymmetric cell divisions
    Cortical force generators are molecular motors orchestrating the correct placement of the mitotic spindle within the cell. To achieve this result, they accomplish different tasks: a) they organize contacts with specialized cortical domains; b) they coordinate in space and time pulling forces acting on astral microtubules; c) they transduce cytosolic and extracellular stimuli instructing the spindle orientation. The core components of force generators and the non-canonical G-protein signaling pathway involved in their regulation are evolutionary conserved. Their central module consist of heterotrimeric NuMA/LGN/Gαi complexes. From a topological point of view, LGN has been depicted as the molecular link between Gαi subunits anchored at the plasma membrane and the Dynein-adaptor NuMA. Recently, we showed that LGN associate with the actin-binding protein Afadin, revealing for the first time an active role of the actomyosin cytoskeleton in stabilising mitotic spindle placement (Carminati, NSMB 2016). We are interested in understanding the signalling pathways and the mechanisms triggering the activation of molecular motors orienting the spindle.

    2. Molecular basis of the interplay between cellular polarity and the division plane
    Our second research line deals with the issue of how force generators are specifically recruited at sites of polarization. In several model systems, cortical polarization is established by the asymmetrical distribution of Par3/Par6/aPKC complexes, which in turn defines the asymmetrical localization of fate determinants. The stem cell adaptor Inscuteable has been described as the key component bridging polarity to spindle motors in stem cell division (Culurgioni, CMLS 2013; Mapelli, Open Biol. 2012; Culurgioni, PNAS 2011). An emerging concept is that cell-autonomous and environmental cues contribute to define the position of the cytokinesis plane during epithelial divisions in order to regulate the proportion of symmetric and asymmetric mitoses. More specifically, Wnt-signaling has emerged as a major driver of oriented asymmetric divisions. We are interested in understanding how asymmetry is specified at a molecular scale, with particular focus on breast and intestinal stem cells.

     

     3. Implications of oriented divisions in cancer development

    Recent reports highlighted the involvement of oriented divisions in progenitor differentiation during mammary gland morphogenesis, as well as intestinal crypt regeneration. However, very little is known to about the molecular mechanisms sustaining oriented divisions in these systems, and how they are deregulated in cancers. We recently started investigating how cortical polarity and spindle alignment pathways affect the asymmetric outcome and the proliferation of mammary stem cell divisions, which we believe will ultimately pertain to breast cancer progression. With the same perspective, a new line of our research activities addresses the molecular events whereby Wnt-signaling promotes oriented divisions of intestinal epithelial cells.

  • Publications

    • Carminati M., Gallini S., Pirovano L., Alfieri A., Bisi S. and Mapelli M. (2016) Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation. Nat. Struct. Mol. Biol., 23,155-63.
    • Gallini S., Carminati M., De Mattia F., Pirovano L., Martini E., Oldani A., Asteriti I.A., Guarguaglini G, Mapelli M. (2016) NuMA phosphorylation orchestrates spindle orientation. Current Biol., 26, 458-69.
    • Santoro A, Vlachou T, Carminati M, Pelicci PG, Mapelli M. (2016) Molecular mechanisms of asymmetric divisions in mammary stem cells. EMBO Rep., 17, 1700-1720.
    • Andersen D.S., Colombani J., Palmerini V., Chakrabandhu K., Röthlisberger M., Toggweiler J., Basler K., Mapelli M., Hueber A., and Léopold P. (2015) The Drosophila TNF receptor Grindelwald couples loss of cell polarity with neoplastic growth. (2015) Nature, 522, 482-6.
    • Culurgioni S., Alfieri A., Pendolino V., Laddomada F. and Mapelli M. (2011) Inscuteable and NuMA proteins bind competitively to Leu-Gly-Asn repeat-enriched protein (LGN) during asymmetric cell divisions. P.N.A.S., 108, 20998-1003.

     

    All publication in pdf file attached

  • Funding

    • 2017 - 2019  Italian Association for Cancer Research (AIRC) Investigator Grant "Wnt-signaling and oriented divisions in normal and cancer intestinal crypts."
    • 2016 - 2019 Ministry of Health, Ricerca Finalizzata "Identification of new therapeutic targets of cancer stem cells: study of the mechanistics of mitotic spindle alignment to cortical polarity in mammary stem cell asymmetric divisions."



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PARTNERSHIP

Università degli Studi di Milano Ecancer Medical Science IFOM-IEO Campus

CREDITS

Ministero della Salute Joint Commission International Breastcertification bollinirosa

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