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 acts as the molecular link between Gαi subunits anchored at the plasma membrane and the Dynein-adaptor NuMA (Pirovano, Nat. Comm. 2019). 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.
Molecular basis of the interplay between cellular polarity and asymmetry
Our second research line deals with the issue of how force generators are specifically recruited at sites of polarization. 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 & Mari, Nat. Comm. 2018; 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.
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 (Culurgioni & Mari, Nat. Comm. 2018). 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.