RESEARCH SUMMARY

Essential physiological processes such as neuronal morphogenesis, cell motility and tissue invasion rely on the spatial and temporal regulation of actin dynamics and therefore, their deregulation is at the root of severe pathologies. Actin reorganization is controlled by nucleation-promoting factors like neural Wiskott-Aldrich syndrome protein (N-WASP) and cortactin, and associated proteins that regulate their activity such as WIP (WASP-interacting protein), a ubiquitously distributed protein that stabilizes actin filaments. Our goal is to define the role of WIP- and WASP-family proteins in actin dynamics within a variety of cellular processes in an array of cell models (fibroblasts, dendritic cells (DC), neurons and astrocytes).

In the past two years, we have contributed toward defining the molecular mechanisms that underlie invasion and extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). We described that WIP is essential for MMP secretion, but not for MMP synthesis, in murine DC. Moreover, absence of WIP prevents the formation of podosomes, actin-rich migratory structures in which MMP activity localizes. Cortactin binding to WIP is required for correct podosome formation, MMP activity and ECM degradation. Our future work aims at unravelling the WIP contribution to invasion and metastasis by human tumour cell lines.

Since the ability to reorganize actin filaments is at the basis of neuronal plasticity, we studied the role of WIP on neuron differentiation both in early and in late developmental stages, in vitro as well as in vivo. Using embryonic hippocampal primary WIP-/- neurons, we characterized, at the biochemical and morphological levels, the effect of WIP as a negative regulator of sprouting and neuritic/dendritic branching without affecting axon generation. Similar to our observations in dendritic cells, we found that WIP expression in neurons is required for the correct cortactin localization. Our results point to WIP as a novel regulator that prevents premature dendritic and synaptic maturation. We aim to deepen our understanding of the contribution of WIP to neuron and astrocyte migration, to brain lamination and development, and the functional effects of WIP deficiency on the murine nervous system.

The results of our work should yield fundamental information on the function of these cytoskeletal molecules and offer new insights into the molecular mechanisms that underlie actin dynamics and related functions, providing new diagnostic and/or therapeutic tools for neurological diseases, inflammation-mediated affections and tumour invasion.