Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites

Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11246-51. doi: 10.1073/pnas.1012401108. Epub 2011 Jun 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / physiology*
  • Calcium Signaling / physiology
  • Cell Nucleus / physiology
  • Cells, Cultured
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology
  • Dendrites / physiology*
  • Equipment Design
  • Genes, fos
  • Humans
  • MAP Kinase Signaling System / physiology
  • Microfluidic Analytical Techniques / instrumentation
  • Microfluidic Analytical Techniques / methods
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neurites / physiology
  • Neuronal Plasticity / physiology
  • Neurons / physiology
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-fos / physiology
  • Rats
  • Signal Transduction / physiology
  • Transcriptional Activation

Substances

  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • activity regulated cytoskeletal-associated protein