title: Differential Maturation of the Two Regulated Secretory Pathways in Human iPSC-Derived Neurons.
abstract: Neurons communicate by regulated secretion of chemical signals from synaptic vesicles (SVs) and dense-core vesicles (DCVs). Here, we investigated the maturation of these two secretory pathways in micro-networks of human iPSC-derived neurons. These micro-networks abundantly expressed endogenous SV and DCV markers, including neuropeptides. DCV transport was microtubule dependent, preferentially anterograde in axons, and 2-fold faster in axons than in dendrites. SV and DCV secretion were strictly Ca2+and SNARE dependent. DCV secretion capacity matured until day in vitro (DIV) 36, with intense stimulation releasing 6% of the total DCV pool, and then plateaued. This efficiency is comparable with mature mouse neurons. In contrast, SV secretion capacity continued to increase until DIV50, with substantial further increase in secretion efficiency and decrease in silent synapses. These data show that the two secretory pathways can be studied in human neurons and that they mature differentially, with DCV secretion reaching maximum efficiency when that of SVs is still low.
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Emperador Melero
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands.
authors.forename: Aishwarya G
authors.initials: AG
authors.lastname: Nadadhur
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands.
authors.forename: Desiree
authors.initials: D
authors.lastname: Schut
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands.
authors.forename: Jan V
authors.initials: JV
authors.lastname: Weering
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands; Department of Pediatrics/Child Neurology, Amsterdam Neuroscience, VU Medical Center, 1081 HV Amsterdam, the Netherlands; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, the Netherlands.
authors.forename: Vivi M
authors.initials: VM
authors.lastname: Heine
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands. Electronic address: ruud.toonen@cncr.vu.nl.
authors.forename: Ruud F
authors.initials: RF
authors.lastname: Toonen
authors.affiliation: Departments of Functional Genomics and Clinical Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit (VU) Amsterdam and VU Medical Center, de Boelelaan 1087, 1081 HV Amsterdam, the Netherlands. Electronic address: matthijs@cncr.vu.nl.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Verhage
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001692:Biological Transport; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D003712:Dendrites / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D050600:SNARE Proteins / Q000378:metabolism; D055571:Secretory Pathway; D022142:Secretory Vesicles / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D015415:Biomarkers; D050600:SNARE Proteins; D002118:Calcium
keywords: dense-core vesicles; human iPSC-derived neurons; neuropeptides; regulated neurosecretion; synaptic transmission