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

Department of Pharmacology, Weill Medical College Cornell University, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2011; 108(27):11246-51. DOI: 10.1073/pnas.1012401108
Source: PubMed


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.

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Available from: Hyung Joon Kim, Jun 02, 2015
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    • "It has been shown that upon BDNF binding, TrkB-positive endosomes undergo dynein-dependent retrograde transport along microtubules to the cell body where TrkB induces survival signals (Watson et al., 1999; Heerssen et al., 2004; Ha et al., 2008), a mechanism studied primarily in axons. Recent technical advances that allow to selectively isolate dendrites from the cell bodies using microfluidic devices (Cohen et al., 2011), facilitated the investigation of the TrkB vesicular retrograde transport in control and HD striatal neurons. A study by Liot et al. shows that upon BDNF stimulation, TrkB binds to htt and dynein in dendrites of cultured striatal neurons, and wild-type htt promotes TrkB transport via dynein-dependent mechanism. "
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    • "The effect of BDNF in the signaling from dendrites to the nucleus depends on MEK1/2 (MAPK and ERK kinase, type 1/ 2), and activity of the TrkB receptors to induce gene expression is required mainly in the soma compartment. However, distinct mechanisms are involved in the regulation of the expression of the two genes since the Ca 2þ concentration in the soma and in the dendritic compartments influenced the expression of Arc but not c- Fos (Cohen et al., 2011). "
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