title: Activity-dependent secretion of progranulin from synapses.
abstract: The secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is co-transported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure.
authors.affiliation: Department of Cellular and Physiological Sciences and the Brain Research Centre, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T-1Z3, Canada.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Petoukhov
authors.forename: Sarah
authors.initials: S
authors.lastname: Fernando
authors.forename: Fergil
authors.initials: F
authors.lastname: Mills
authors.forename: Farhan
authors.initials: F
authors.lastname: Shivji
authors.forename: Diana
authors.initials: D
authors.lastname: Hunter
authors.forename: Charles
authors.initials: C
authors.lastname: Krieger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silverman
authors.forename: Shernaz X
authors.initials: SX
authors.lastname: Bamji
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D004622:Embryo, Mammalian; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000077153:Progranulins; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D022142:Secretory Vesicles / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C084619:Grn protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011498:Protein Precursors
keywords: Activity; Frontotemporal dementia; Hippocampal culture; Progranulin; Protein trafficking; Secretion; Synapses