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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 27; pp. 11246 - 11251
• Main Authors: Cohen, Michael S, Orth, Carlos Bas, Kim, Hyung Joon, Jeon, Noo Li, Jaffrey, Samie R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.07.2011; National Acad Sciences
• Subjects: Animals; Axons; Biological Sciences; Brain; Brain-Derived Neurotrophic Factor - physiology; Calcium; Calcium Signaling - physiology; Cell Nucleus - physiology; Cells; Cells, Cultured; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - physiology; Dendrites; Dendrites - physiology; Equipment Design; genes; Genes, fos; Humans; Long term potentiation; MAP Kinase Signaling System - physiology; Messenger RNA; Microfluidic Analytical Techniques - instrumentation; Microfluidic Analytical Techniques - methods; Microfluidic devices; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurites; Neurites - physiology; Neuronal Plasticity - physiology; Neurons; Neurons - physiology; Neuroscience; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-fos - physiology; Rats; Receptors; Signal transduction; Signal Transduction - physiology; Transcriptional Activation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1012401108

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.