COMITPOL

Understanding the coordination between mitosis and cell polarity in Drosophila

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Shaping the tissues that make an organism requires a tight control of cell division and mechanisms that spatially distribute signalling cues and adhesive structures within single cells. Although cell division and polarity have been extensively studied, how these processes are coordinated is largely unknown.

The primary goal of this project is to understand the link between regulation of mitotic cell division and the organization of polarity at the organism level. First, we will use the Drosophila follicle epithelium to set up an in vivo model to address with high temporal resolution how the evolutionary conserved polarity complexes are remodelled at the cell cortex during mitosis in epithelia. We will then characterize the specific function of distinct types of mitotic proteins (Polo, Aurora A, BubR1 and Ndc80) in the organization of the follicle epithelium polarity and architecture, and in germline stem cell asymmetric division. The study in the follicle epithelium will contribute for the understanding of the mechanisms that coordinate the establishment of a mitotic spindle with changes in cortical polarity. In addition, the comparison between these two contexts with distinct cellular features will elucidate the specific requirements of the different mitotic genes.

Misregulation of cell division and loss of epithelial organization are a hallmark of cancer. We will therefore test the interaction between polarity proteins and cell cycle regulators to explore new hypothesis for tumour progression. For this purpose, we will determine the ability to overproliferate, invade and metastasize of tissues where we simultaneously interfered with mitosis and polarity. Thus, this work will have implications for human disease, shedding light on the mechanisms of tumorigenesis.'

Introduzione (Teaser)

A cell has distinct poles and must be joined to its neighbours so they communicate nutrients, waste and chemical messages. Failure of organisation at this level can have dire consequences.

Descrizione progetto (Article)

Examples of the seriousness for the organism if polarity is not adhered to can be seen in human epithelia, linings of organs. Epithelia are the source of most cancers and defects in apico-basal organisation are accompanied by poor prognosis. Another example is that absorption of nutrients in the gut has to have a polarised direction.

The 'Understanding the coordination between mitosis and cell polarity in Drosophila' (COMITPOL) project investigated how polarity is conserved during cell growth division, mitosis. Physically splitting the cell by cytokinesis presents many challenges as organisation of polarity must take into account dramatic cytoskeleton reorganisation. Furthermore, the scientists explored if division of the cytoplasm or cytokinesis is associated with loss of polarity during tumour formation.

Protein complexes at cell-cell junctions, Adherens junctions, show a polarised distribution in epithelia and are linked to the actin cytoskeleton that maintains cell shape. Using both time-lapse movies of intact Drosophila ovaries and three-dimensional reconstructions of fixed samples, COMITPOL researchers found that the apical localisation of Adherens junctions also determines the asymmetry of cytokinesis in order to maintain epithelial architecture during proliferation.

The scientists also investigated the organisation of other key polarity determinants, such as the tumour suppressor Lgl. Altered expression of cell adhesion and polarity proteins has been associated with epithelial transformation and human cancer. Mitotic kinase Aurora A redirects the polarity protein Lethal giant larvae (Lgl) to a new subcellular localization in the cell during mitosis.

The work has been published in peer-reviewed journals including EMBO reports and Cell Cycle. Looking at proteins involved in conservation of polarity during mitosis is a research path leading towards targeted therapies. Continued research on polarity and tumour progression is planned thanks to funding from the Portuguese Foundation for Science and Technology. Findings promise further discoveries relevant to human disease.