CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

From filopodia to synapses: the cell biology of neuronal wiring

The interest of the laboratory is to identify the molecular processes controlling the formation and the function of synaptic contacts between neurons. The process of synaptogenesis is crucial to the development of the nervous system, but the molecular pathways that regulate this process are not fully understood. It is well known that the regulation of neuronal filopodia plays a crucial role during development and synaptogenesis. Axonal and dendritic filopodia, which generate presynaptic and postsynaptic compartments respectively, are formed by actin filaments, whose dynamic formation and topological organization are controlled by a set of actin binding proteins which play different functional roles in regulating actin dynamics. In the last years, we have demostrated the role of actin capping proteins in controlling the formation of axonal and dendritic filopodia in neuronal cells and described a novel molecular mechanism that links extracellular signals to neuronal morphology (Menna et al, 2009).

 

External cues, such as brain-derived neurotrophic factor (BDNF), trigger synaptogenesis by promoting the formation of axonal filopodia. We have revealed a novel molecular circuit underlying BDNF-stimulated filopodia formation through the regulated inhibition of actincapping factor activity. We showed that the actin-capping protein Eps8 down-regulates axonal filopodia formation in neurons in the absence of neurotrophic factors. In contrast, in the presence of BDNF, the kinase MAPK becomes activated and phosphorylates Eps8, leading to inhibition of its actin-capping function and stimulation of filopodia formation, a process with crucial impacts on neuronal development (Menna et al, 2009).

Moreover we found that Eps8 prevalently acts as a capper in neurons whereas it plays a major role as a bundler, and not as a capper, in non neuronal cells. (Vaggi et al 2011). In line with the role of filopodia in generating synaptic contacts, the increased number of filopodia in Eps8 deficient mice results in enhanced formation of pre and postsynaptic specializations. Eps8 deficient mice exhibit impaired spatial and episodic memory, associated with defects in activity-dependent plasticity phenomena and immature features of spine morphology. These data identify Eps8 as a critical capping protein in the regulation of filopodia and synapse formation and indicate that deficits in Eps8-mediated actin-based dynamics may originate defects in activity-dependent synaptogenesis, eventually impacting learning processes (Menna et al., 2011).

Publications

  • Menna E, Fossati G, Scita G, Matteoli M (2011) From filopodia to synapses: the role of actin-capping and anti-capping proteins. Eur. J. Neurosci. 34:1655-62.
  • Vaggi F, Disanza A, Milanesi F, Di Fiore PP, Menna E, Matteoli M, Gov NS, Scita G, Ciliberto A (2011) The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation. PLoS Comput. Biol. 7:e1002088.
  • Menna E, Disanza A, Cagnoli C, Schenk U, Gelsomino G, Frittoli E, Hertzog M, Offenhauser N, Sawallisch C, Kreienkamp HJ, Gertler FB, Di Fiore PP, Scita G, Matteoli M (2009) Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS Biol. 7:e1000138.
  • Schenk U, Menna E, Kim T, Passafaro M, Chang S, De Camilli P, Matteoli M (2005) A novel pathway for presynaptic mitogen-activated kinase activation via AMPA receptors. J. Neurosci. 25:1654-63.

Collaborations

  • Michela Matteoli, Department of Medical Pharmacology, University of Milan, Milan, Italy
  • Giorgio Scita, Andrea Disanza, Andrea Ciliberto, IFOM Milano
  • M.E. Sala, Department of Medical Pharmacology, University of Milan, Milan, Italy
  • Maura Francolini, Department of Medical Pharmacology, University of Milan, Milan, Italy
  • Carolina Frassoni, Istituto Neurologico “Besta”Milano
  • Erick Wanker and Angeli Moeller, Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin

 

PI photo

Elisabetta Menna

Contact information

email  E-mail

email  +39 02 50317009

Participating staff

Raffaella Morini

Stefania Zambetti