title: Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites.
abstract: Signaling from dendritic synapses to the nucleus regulates important aspects of neuronal function, including synaptic plasticity. The neurotrophin brain-derived neurotrophic factor (BDNF) can induce long-lasting strengthening of synapses in vivo and this effect is dependent on transcription. However, the mechanism of signaling to the nucleus is not well understood. Here we describe a microfluidic culture device to investigate dendrite-to-nucleus signaling. Using these microfluidic devices, we demonstrate that BDNF can act directly on dendrites to elicit an anterograde signal that induces transcription of the immediate early genes, Arc and c-Fos. Induction of Arc is dependent on dendrite- and cell body-derived calcium, whereas induction of c-Fos is calcium-independent. In contrast to retrograde neurotrophin-mediated axon-to-nucleus signaling, which is MEK5-dependent, BDNF-mediated anterograde dendrite-to-nucleus signaling is dependent on MEK1/2. Intriguingly, the activity of TrkB, the BDNF receptor, is required in the cell body for the induction of Arc and c-Fos mediated by dendritically applied BDNF. These results are consistent with the involvement of a signaling endosome-like pathway that conveys BDNF signals from the dendrite to the nucleus.
authors.affiliation: Department of Pharmacology, Weill Medical College Cornell University, New York, NY 10065, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Carlos
authors.initials: C
authors.lastname: Bas Orth
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.forename: Samie R
authors.initials: SR
authors.lastname: Jaffrey
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D003712:Dendrites / Q000502:physiology*; D004867:Equipment Design; D016762:Genes, fos; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation / Q000379:methods; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D016501:Neurites / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology; D014176:Protein Biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; C092069:activity regulated cytoskeletal-associated protein