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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    ABSTRACT: The striatum, a major component of the basal ganglia, performs multiple functions including control of movement, reward, and addiction. Dysfunction and death of striatal neurons are the main causes for the motor disorders associated with Huntington's disease (HD). Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is among factors that promote survival and proper function of this neuronal population. Here, we review recent studies showing that BDNF determines the size of the striatum by supporting survival of the immature striatal neurons at their origin, promotes maturation of striatal neurons, and facilitates establishment of striatal connections during brain development. We also examine the role of BDNF in maintaining proper function of the striatum during adulthood, summarize the mechanisms that lead to a deficiency in BDNF signaling and subsequently striatal degeneration in HD, and highlight a potential role of BDNF as a therapeutic target for HD treatment.
    Frontiers in Cellular Neuroscience 08/2014; 8:254. DOI:10.3389/fncel.2014.00254 · 4.29 Impact Factor
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    • "To induce neuronal differentiation of hESC-derived neurospheres, cells were attached to a PLO/FN-coated Type 2 device (Fig. 1), in differentiation medium containing BDNF, which promotes neuronal differentiation (Cohen et al., 2011). Figure 4A shows representative morphological features of neurospheres following attachment, with extensive neurite outgrowth at the periphery of neurospheres. "
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    ABSTRACT: Microfluidics can provide unique experimental tools to visualize the development of neural structures within a microscale device, which is followed by guidance of neurite growth in the axonal isolation compartment. We utilized microfluidics technology to monitor the differentiation and migration of neural cells derived from human embryonic stem cells (hESCs). We co-cultured hESCs with PA6 stromal cells, and isolated neural rosette-like structures, which subsequently formed neurospheres in suspension culture. Tuj1-positive neural cells, but not nestinpositive neural precursor cells (NPCs), were able to enter the microfluidics grooves (microchannels), suggesting that neural cell-migratory capacity was dependent upon neuronal differentiation stage. We also showed that bundles of axons formed and extended into the microchannels. Taken together, these results demonstrated that microfluidics technology can provide useful tools to study neurite outgrowth and axon guidance of neural cells, which are derived from human embryonic stem cells.
    Molecules and Cells 06/2014; 37(6). DOI:10.14348/molcells.2014.0137 · 2.09 Impact Factor
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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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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin is thought to act at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.
    Neuropharmacology 04/2013; 76. DOI:10.1016/j.neuropharm.2013.04.005 · 5.11 Impact Factor
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