Activity-dependent secretion of progranulin from synapses

J Cell Sci. 2013 Dec 1;126(Pt 23):5412-21. doi: 10.1242/jcs.132076. Epub 2013 Sep 17.


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.

Keywords: Activity; Frontotemporal dementia; Hippocampal culture; Progranulin; Protein trafficking; Secretion; Synapses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Dendrites / metabolism*
  • Embryo, Mammalian
  • Gene Expression
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Progranulins
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Secretory Vesicles / metabolism
  • Synapses / metabolism
  • Synaptic Vesicles / metabolism


  • Brain-Derived Neurotrophic Factor
  • Grn protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Protein Precursors