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First published online 21 October 2008
doi: 10.1242/jcs.033803

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Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones

Dario Bonanomi^1,*,, Eugenio F. Fornasiero^1,*, Gregorio Valdez^2,, Simon Halegoua², Fabio Benfenati^3,4,5, Andrea Menegon¹ and Flavia Valtorta^1,5,¶

¹ S. Raffaele Scientific Institute/Vita-Salute University and IIT Unit of Molecular Neuroscience, 20132 Milano, Italy
² Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
³ Department of Experimental Medicine, University of Genova, 16132 Genova, Italy
⁴ Department of Neuroscience and Brain Technologies, IIT Central Laboratories, 16163 Genova, Italy
⁵ Istituto Nazionale di Neuroscienze, 10125 Torino, Italy

^¶ Author for correspondence (e-mail: valtorta.flavia{at}hsr.it)

Accepted 12 August 2008

The growth-cone plasma membrane constantly reconfigures during axon navigation and upon target recognition. The identity and regulation of the membrane pathway(s) participating in remodeling of the growth-cone surface remain elusive. Here, we identify a constitutive, high-capacity plasma-membrane-recycling activity in the axonal growth cones, which is mediated by a novel bulk endocytic pathway that is mechanistically related to macropinocytosis. This pathway generates large compartments at sites of intense actin-based membrane ruffling through the actions of phosphatidylinositol 3-kinase, the small GTPase Rac1 and the pinocytic chaperone Pincher. At early developmental stages, bulk endocytosis is the primary endocytic pathway for rapid retrieval of the growth-cone plasma membrane. At later stages, during the onset of synaptogenesis, an intrinsic program of maturation leads to downregulation of basal bulk endocytosis and the emergence of depolarization-induced synaptic-vesicle exo-endocytosis. We propose that the control of bulk membrane retrieval contributes to the homeostatic regulation of the axonal plasma membrane and to growth-cone remodeling during axonal outgrowth. In addition, we suggest that the downregulation of bulk endocytosis during synaptogenesis might contribute to the preservation of synaptic-vesicle specificity.

Key words: Endocytosis, Axolemma, Synaptic vesicle, Trafficking, Fluorescence microscopy

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				D. Bonanomi, E. F. Fornasiero, G. Valdez, S. Halegoua, F. Benfenati, A. Menegon, and F. Valtorta Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones Development, December 1, 2008; 135(23): e1 - e1. [Full Text]