Regulated transport of signaling proteins from synapse to nucleus

Herbst, Wendy A.; Martin, Kelsey C.

doi:10.1016/j.conb.2017.04.006

Cited by 35 publications

(22 citation statements)

References 46 publications

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“…One proposed mechanism for synapse-to-nucleus communication is through regenerative ER Ca 2+ waves, mediated by ryanodine and IP 3 receptors that release Ca 2+ from the ER ( Hagenston and Bading, 2011 ; Herbst and Martin, 2017 ; Panayotis et al, 2015 ; Ross, 2012 ). We have shown here that 1 Hz-GU activates NMDARs and LTCCs, both of which we have previously shown to induce CICR in dendrites ( Dittmer et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…In the second, the “molecular translocation model,” signaling molecules activated postsynaptically translocate in mobile molecular signaling complexes from dendrites to the nucleus via diffusion or molecular transport mechanisms over much longer timescales ( Ch’ng et al, 2012 , 2015 ; Dinamarca et al, 2016 ; Panayotis et al, 2015 ; Zhai et al, 2013 ). In the third, the “Ca 2+ -wave model,” regenerative endoplasmic reticulum (ER) Ca 2+ waves that are initiated near the synapse by ryanodine or IP 3 receptors can spread to the soma via Ca 2+ -induced Ca 2+ release (CICR) to elevate somatic Ca 2+ and activate somato-nuclear signaling factors ( Hagenston and Bading, 2011 ; Herbst and Martin, 2017 ; Panayotis et al, 2015 ; Ross, 2012 ). Each of these routes of communication are thought to be activated by different patterns of synaptic stimuli and may encode distinct temporal and source specific information, depending on both the subcellular origin of the molecular signals and the time taken for these signals to reach the nucleus.…”

Section: Introductionmentioning

confidence: 99%

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Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca2+ Channel Ca2+ Spike Propagation to the Soma

et al. 2019

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SUMMARY Long-term information storage in the brain requires continual modification of the neuronal transcriptome. Synaptic inputs located hundreds of micrometers from the nucleus can regulate gene transcription, requiring high-fidelity, long-range signaling from synapses in dendrites to the nucleus in the cell soma. Here, we describe a synapse-to-nucleus signaling mechanism for the activity-dependent transcription factor NFAT. NMDA receptors activated on distal dendrites were found to initiate L-type Ca 2+ channel (LTCC) spikes that quickly propagated the length of the dendrite to the soma. Surprisingly, LTCC propagation did not require voltage-gated Na + channels or back-propagating action potentials. NFAT nuclear recruitment and transcriptional activation only occurred when LTCC spikes invaded the somatic compartment, and the degree of NFAT activation correlated with the number of somatic LTCC Ca 2+ spikes. Together, these data support a model for synapse to nucleus communication where NFAT integrates somatic LTCC Ca 2+ spikes to alter transcription during periods of heightened neuronal activity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca2+ Channel Ca2+ Spike Propagation to the Soma

et al. 2019

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“…Many of the changes described above occur at the same time as axons have reached their targets and synapses are forming and maturing. Signalling to the nucleus from the postsynaptic side of synapses in dendrites or from the presynaptic side in axons is a strong candidate, and several signalling pathways that affect neuronal gene expression have been identified which would be candidates for driving the neuronal maturation process [57,99]. Overall, it appears that for neurons to express a regeneration transcriptional programme the right transcription factors must be expressed and present in the nucleus.…”

Section: Genetics and Epigeneticsmentioning

confidence: 99%

The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Fawcett

2019

Neurochem Res

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Axon regeneration in the CNS is inhibited by many extrinsic and intrinsic factors. Because these act in parallel, no single intervention has been sufficient to enable full regeneration of damaged axons in the adult mammalian CNS. In the external environment, NogoA and CSPGs are strongly inhibitory to the regeneration of adult axons. CNS neurons lose intrinsic regenerative ability as they mature: embryonic but not mature neurons can grow axons for long distances when transplanted into the adult CNS, and regeneration fails with maturity in in vitro axotomy models. The causes of this loss of regeneration include partitioning of neurons into axonal and dendritic fields with many growth-related molecules directed specifically to dendrites and excluded from axons, changes in axonal signalling due to changes in expression and localization of receptors and their ligands, changes in local translation of proteins in axons, and changes in cytoskeletal dynamics after injury. Also with neuronal maturation come epigenetic changes in neurons, with many of the transcription factor binding sites that drive axon growth-related genes becoming inaccessible. The overall aim for successful regeneration is to ensure that the right molecules are expressed after axotomy and to arrange for them to be transported to the right place in the neuron, including the damaged axon tip.

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“…In postnatal development, experience‐dependent neural activity induces transcriptional programs that sculpt neural circuits by regulating synapse development and plasticity . The complex dialogue between the synapse and the nucleus involves diverse adhesion molecules, scaffolding proteins, and chromatin regulators, many of which have been implicated in neurodevelopmental disorders, such as ASD . Thus, perturbation of the mechanisms that regulate gene expression at a genomic level may affect the development of the nervous system during the earliest stages, causing global disruption in neuronal differentiation and wiring or, at later time‐points, causing abnormalities in synaptic function or activity‐dependent processes that underlie learning or more complex aspects of information processing in the developed brain.…”

Section: Gene Regulation In the Brain: Unique Strategies And New Methmentioning

confidence: 99%

Gene regulatory mechanisms underlying sex differences in brain development and psychiatric disease

Manoli

Tollkühn

2018

Annals of the New York Academy of Sciences

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The sexual differentiation of the mammalian nervous system requires the precise coordination of the temporal and spatial regulation of gene expression in diverse cell types. Sex hormones act at multiple developmental time points to specify sex-typical differentiation during embryonic and early development and to coordinate subsequent responses to gonadal hormones later in life by establishing sex-typical patterns of epigenetic modifications across the genome. Thus, mutations associated with neuropsychiatric conditions may result in sexually dimorphic symptoms by acting on different neural substrates or chromatin landscapes in males and females. Finally, as stress hormone signaling may directly alter the molecular machinery that interacts with sex hormone receptors to regulate gene expression, the contribution of chronic stress to the pathogenesis or presentation of mental illness may be additionally different between the sexes. Here, we review the mechanisms that contribute to sexual differentiation in the mammalian nervous system and consider some of the implications of these processes for sex differences in neuropsychiatric conditions.

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Regulated transport of signaling proteins from synapse to nucleus

Cited by 35 publications

References 46 publications

Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca2+ Channel Ca2+ Spike Propagation to the Soma

Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca2+ Channel Ca2+ Spike Propagation to the Soma

The Struggle to Make CNS Axons Regenerate: Why Has It Been so Difficult?

Gene regulatory mechanisms underlying sex differences in brain development and psychiatric disease

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