Astrocyte Polarity and Migration – Cell Polarity

Cell migration is a fundamental process during development and in the adult where is allows delivery of immune cells to infection sites, wound healing or else dissemination of tumour cells during metastasis. Establishment, orientation and regulation of cell polarity play a key role in the initiation and the regulation of migration. Cell polarity basically corresponds to the spatial organization of intracellular organites along a favoured cell axis defined by the centrosome and the nucleus position. Our research project aims at determining the molecular mechanisms controlling cell polarization and their role in cell migration. We are particularly interested in cell migration within the central nervous system (CNS). Astrocytes are the major glial cells of the CNS. They fulfill a wide range of functions contributing to neuronal development and functions. Following cerebral lesions, astrocytes polarize and migrate to participate to the glial scar which limits cerebral regions accessible to axonal regeneration. Astrocyte can also give rise to brain tumors exhibit a strong ability to invade the surrounding tissue. By developing new in vitro polarization models and by using a variety of cellular models, we aim at studying the regulation of astrocyte polarization and migration. We have previously deciphered a 'polarity pathway' that is controlled by cell adhesion to the extracellular matrix. In this project we plan: - to further characterize integrin-induced polarity pathway. We will focus our study on the regulation of the small GTPase Cdc42 which is a major regulator of cell polarity from yeast to mammals. - to determine how extracellular stimuli such as soluble chemoattractants or intercellular contacts can modulate this pathway to regulate cell polarity and cell migration. We will, in particular, investigate the role of astrocyte interactions with neighboring neuronal or non neuronal cells in the regulation of astrocyte polarity and migration - to study if and how polarization of the microtubule network, which plays a key role in astrocyte migration, can induce the polarization the other cytoskeletal networks (actin microfilaments and intermediate filaments) in order to promote cell migration. This project should help us define very fundamental molecular mechanisms controlling cell polarization. This project also aims at characterizing the molecular mechanisms specifically controlling astrocyte polarization and migration in order to better understand the migratory behaviors associated with cerebral responses to trauma and brain tumor dissemination and identify potential therapeutic targets that will help us control astrocyte and brain tumor dissemination. This should eventually lead to the identification of molecular therapeutic targets in order to modulate astrocyte or glioma migration.