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

• Published in: Journal of cell science Vol. 121; no. 22; pp. 3757 - 3769
• Main Authors: Bonanomi, Dario, Fornasiero, Eugenio F, Valdez, Gregorio, Halegoua, Simon, Benfenati, Fabio, Menegon, Andrea, Valtorta, Flavia
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 15.11.2008
• Subjects: Animals; Cell Membrane - metabolism; Cells, Cultured; Endocytosis; Growth Cones - metabolism; Hippocampus - cytology; Hippocampus - growth & development; Hippocampus - metabolism; Mice; Mice, Inbred C57BL; Neurogenesis; Neurons - cytology; Neurons - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction; Synaptic Vesicles - metabolism
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.033803

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.