RIVELINE Daniel

Synthetic polyamines promote self-organisation of actin network

 

Cellular protrusions involve self-organisation processes that are driven by site-directed assembly of actin filaments. So far, only chemical compounds depolymerizing actin or stabilizing filaments have been used to eliminate the formation of protrusions. With J.M. Lehn Lab. (ISIS) and with M.F. Carlier Lab. (LEBS), we have reported the design of polyamines (macrocyclic and branched acyclic), and we showed that they enter the cell and induce specific growth of actin-enriched lamellipodia within minutes (Nedeva et al., 2013). We showed that these polyamines specifically target actin both in vitro and in vivo.

This discovery results from a collaboration initiated in Strasbourg and these compounds provide new and unprecedented opportunities to study actin cytoskeleton in morphogenetic processes and in vitro systems with potential medical applications. The compounds pave the way towards artificial supramolecular systems with control of actin architecture and dynamics through Chemistry. Also they will act as key molecules for revealing molecular regulations within cells for actin cytoskeleton. As such they will give insight into the design of artificial supramolecular dynamics networks. 

This project proposes to probe the wide potential of these synthetic polyamines on the following molecular systems to establish their strengths and potential relevance for artificial molecular architecture in cells ; preliminary experiments have shown encouraging effects.

(i) Epithelial MDCK cells : these monolayers are good model for tissues in vivo; we will probe the dynamics of the different polyamines for formation and evolution of colonies and monolayers where actin plays a key role; effects of the drugs will be probed in the presence of inhibitors of the Rho/Rac/cdc42 pathway to dissect molecular mechanisms of regulation;

(ii) fission yeast : a powerful model system for genetic manipulations, actin is involved in endocytosis and in the cytokinetic ring closure in particular. We will probe both phenomena in the presence of compounds with combinations of mutants in the actin cytoskeleton and their impacts in self-organisation of the actin cytoskeleton.

These new studies will reveal new dynamics of molecular regulations in cells. Few specific drugs targeted to the cytoskeleton are available. This new Strasbourg supramolecular compounds with self-organisation properties on biomatter could open another international visibility in the field.