Asymmetric Cell Divisions
We are interested in the molecular mechanisms governing asymmetric stem cell divisions, with emphasis on the role of the mitotic orientation in determining daughter cells' fate. The proper execution of asymmetric divisions is crucial in generating tissue diversity during development, and for tissue homeostasis and regeneration in adult organisms. Failures in asymmetric divisions cause abnormal proliferation, 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. Our activity is organized in three main research lines:

1. Study of molecular machines coordinating oriented cell divisions. The correct placement of the mitotic spindle within the cell is orchestrated by Dynein-based microtubule motors able to organize contacts with specialized cortical domains, and coordinate pulling forces acting on astral microtubules. The central module of these motors consists of conserved heterotrimeric NuMA/LGN/Gαi complexes, which are major focus of our studies (Carminati, NSMB 2016; Gallini, Curr Biol 2016).

2. Interplay between cellular polarity, orientation and asymmetry
. Our second research line addresses how epithelial polarity instructs orientation and asymmetric fate. In this context, we study the stem cell protein Inscuteable (Culurgioni, CMLS 2013; Mapelli, Open Biol. 2012; Culurgioni, PNAS 2011). Recently Wnt-signaling has emerged as a major driver of oriented asymmetric divisions. We investigate 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. Oriented divisions contribute to mammary gland morphogenesis and intestinal crypt regeneration. However, little is known about the mechanisms underlying orientation in these systems, and how they are deregulated in cancers. We started investigating how orientation affects asymmetry in mammary stem cell divisions, which we believe will ultimately pertain to breast cancer progression (Culurgioni & Mari, Nat Commun 2018). With the same perspective, we addresses the molecular events whereby Wnt-signaling promotes oriented divisions of intestinal epithelial cells in normal and pathological conditions.
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