A Retrograde Neuronal Survival Response: Target-Derived Neurotrophins Regulate MEF2D and bcl-w

Pazyra-Murphy, Maria F.; Hans, Aymeric; Courchesne, Stephanie L.; Karch, Christoph; Cosker, Katharina E.; Heerssen, Heather M.; Watson, Fiona; Kim, Tae Kyung; Greenberg, Michael E.; Segal, Rosalind A.

doi:10.1523/jneurosci.0233-09.2009

Cited by 68 publications

(61 citation statements)

References 71 publications

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“…S5), indicating that the effects of BDNF do not reflect retrograde signaling from axons to the nucleus. Importantly, previous studies using Campenot chambers, where the distance between axons and cell bodies is 1 mm, have shown that neurotrophins can convey signals from axons to the nucleus in peripheral system neurons within the time course of our experiments (22,23).…”

Section: Resultsmentioning

confidence: 71%

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

Cohen

Bas‐Orth

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.gene expression | mRNA translation

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Section: Resultsmentioning

confidence: 71%

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

Cohen

Bas‐Orth

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Further, the technical challenge of delivering interfering molecules (i.e., siRNAs) efficiently into neurons has also been only more recently addressed. Existing literature suggests a role of ERK5 in neuronal development (Cundiff et al 2009), adult neurogenesis in hippocampus and the olfactory bulb Pan et al 2013), neuronal survival in both CNS and PNS (Watson et al 2001;Pazyra-Murphy et al 2009), and neuropathic pain in the spine (Obata et al 2007). A few studies have identified neurotrophins, including NGF, BDNF and NT-3 as major physiological activators of ERK5 in neurons (Watson et al 2001;Wang et al 2006b;Ohtsuka et al 2009;Yu et al 2012).…”

Section: Discussionmentioning

confidence: 99%

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Sun

Cunningham

et al. 2014

AGE

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Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H 2 O 2 )-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H 2 O 2 -caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC.Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF-or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H 2 O 2 -stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death.

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“…1). Addition of neurotrophins to distal axons, but not cell bodies, also enhances activation of the transcription factor MEF2D by a Trk-dependent ERK5 pathway (18). Together, ERK5 and MEF2D increase expression of the antiapoptotic protein bcl-w, MEF2D, and other retrograde response genes.…”

Section: Diverse Receptor Families Signal From Endosomes (Summarized Inmentioning

confidence: 96%

“…Difficulties in studying endosomal signaling in cells in primary culture or in intact animals include detection of signaling molecules, which are often expressed at low levels, and discrimination between plasma membrane and endosomal signaling events. Promising approaches include studies of mice expressing fluorescently tagged receptors (99) or lacking key endosomal signaling proteins (87), siRNA knockdown of signaling intermediates in neurons (18), use of innovative methods to isolate endosomal signaling complexes (4,55), and studies of agonists that selectively activate endosomal rather than plasma membrane signaling pathways (89)(90)(91).…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Endosomes: A legitimate platform for the signaling train

Murphy

Padilla

Hasdemir

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

343

339

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Although long regarded as a conduit for the degradation or recycling of cell surface receptors, the endosomal system is also an essential site of signal transduction. Activated receptors accumulate in endosomes, and certain signaling components are exclusively localized to endosomes. Receptors can continue to transmit signals from endosomes that are different from those that arise from the plasma membrane, resulting in distinct physiological responses. Endosomal signaling is widespread in metazoans and plants, where it transmits signals for diverse receptor families that regulate essential processes including growth, differentiation and survival. Receptor signaling at endosomal membranes is tightly regulated by mechanisms that control agonist availability, receptor coupling to signaling machinery, and the subcellular localization of signaling components. Drugs that target mechanisms that initiate and terminate receptor signaling at the plasma membrane are widespread and effective treatments for disease. Selective disruption of receptor signaling in endosomes, which can be accomplished by targeting endosomal-specific signaling pathways or by selective delivery of drugs to the endosomal network, may provide novel therapies for disease.signal transduction ͉ trafficking ͉ endocytosis ͉ receptors

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A Retrograde Neuronal Survival Response: Target-Derived Neurotrophins Regulate MEF2D and bcl-w

Cited by 68 publications

References 71 publications

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

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

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

Endosomes: A legitimate platform for the signaling train

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