Tumor suppressor menin mediates peripheral nerve injury-induced neuropathic pain through potentiating synaptic plasticity

Xu, Shunqing; Wu, Hai‐Yin; Wang, X.; Shen, Xiaofeng; Guo, Xirong; Shen, Rong; Wang, F.

doi:10.1016/j.neuroscience.2012.07.036

Cited by 15 publications

(22 citation statements)

References 56 publications

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“…In addition to our findings in the CNS, Xu et al (2012) discovered a potential role of menin in the peripheral nervous system. They found that menin was upregulated in the spinal cord following peripheral nerve injury, and contributed to neuropathic hypersensitivity in mice by potentiating synaptic plasticity in neurons of the dorsal horn [35] , [36] . Together with our study, it is thus reasonable to conclude that menin plays a role in synaptic physiology in both invertebrate and vertebrate species.…”

Section: Discussionmentioning

confidence: 99%

Menin: A Tumor Suppressor That Mediates Postsynaptic Receptor Expression and Synaptogenesis between Central Neurons of Lymnaea stagnalis

et al. 2014

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Neurotrophic factors (NTFs) support neuronal survival, differentiation, and even synaptic plasticity both during development and throughout the life of an organism. However, their precise roles in central synapse formation remain unknown. Previously, we demonstrated that excitatory synapse formation in Lymnaea stagnalis requires a source of extrinsic NTFs and receptor tyrosine kinase (RTK) activation. Here we show that NTFs such as Lymnaea epidermal growth factor (L-EGF) act through RTKs to trigger a specific subset of intracellular signalling events in the postsynaptic neuron, which lead to the activation of the tumor suppressor menin, encoded by Lymnaea MEN1 (L-MEN1) and the expression of excitatory nicotinic acetylcholine receptors (nAChRs). We provide direct evidence that the activation of the MAPK/ERK cascade is required for the expression of nAChRs, and subsequent synapse formation between pairs of neurons in vitro. Furthermore, we show that L-menin activation is sufficient for the expression of postsynaptic excitatory nAChRs and subsequent synapse formation in media devoid of NTFs. By extending our findings in situ, we reveal the necessity of EGFRs in mediating synapse formation between a single transplanted neuron and its intact presynaptic partner. Moreover, deficits in excitatory synapse formation following EGFR knock-down can be rescued by injecting synthetic L-MEN1 mRNA in the intact central nervous system. Taken together, this study provides the first direct evidence that NTFs functioning via RTKs activate the MEN1 gene, which appears sufficient to regulate synapse formation between central neurons. Our study also offers a novel developmental role for menin beyond tumour suppression in adult humans.

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Section: Discussionmentioning

confidence: 99%

Menin: A Tumor Suppressor That Mediates Postsynaptic Receptor Expression and Synaptogenesis between Central Neurons of Lymnaea stagnalis

et al. 2014

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“…For example, we observed up-regulation of transcripts encoding putative homologs of menin/SCG2 (menin like, GenBank: EB264888.1) IGF2 (insulin-like growth factor 2, GenBank: GD220814), and FGFr-4 (fibroblast growth factor receptor 4-like, GenBank: CK323234). Menin up-regulation is essential for spinal plasticity expressed after peripheral nerve injury (Xu et al 2012). Insulin-like growth factor 2 (IGF2) helps mediate inhibitory-avoidance learning in rat and can even serve as a memory enhancer (Chen et al 2011).…”

Section: Changes In Neuronal Functionmentioning

confidence: 99%

Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica

et al. 2017

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We characterized the transcriptional response accompanying maintenance of long-term sensitization (LTS) memory in the pleural ganglia of using microarray ( = 8) and qPCR ( = 11 additional samples). We found that 24 h after memory induction there is strong regulation of 1198 transcripts (748 up and 450 down) in a pattern that is almost completely distinct from what is observed during memory encoding (1 h after training). There is widespread up-regulation of transcripts related to all levels of protein production, from transcription (e.g., subunits of transcription initiation factors) to translation (e.g., subunits of eIF1, eIF2, eIF3, eIF4, eIF5, and eIF2B) to activation of components of the unfolded protein response (e.g., CREB3/Luman, BiP, AATF). In addition, there are widespread changes in transcripts related to cytoskeleton function, synaptic targeting, synaptic function, neurotransmitter regulation, and neuronal signaling. Many of the transcripts identified have previously been linked to memory and plasticity (e.g., Egr, menin, TOB1, IGF2 mRNA binding protein 1/ZBP-1), though the majority are novel and/or uncharacterized. Interestingly, there is regulation that could contribute to metaplasticity potentially opposing or even eroding LTS memory (down-regulation of adenylate cyclase and a putative serotonin receptor, up-regulation of FMRFa and a FMRFa receptor). This study reveals that maintenance of a "simple" nonassociative memory is accompanied by an astonishingly complex transcriptional response.

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“…In Lymnaea central neurons, we found that L -menin and its amino (N)-terminal and carboxyl (C)-terminal fragments exhibited differential subcellular localization, and coordinated the transcriptional expression and functional clustering of L -nAChRs during cholinergic synaptogenesis 6 . As a synaptogenic function for menin is found from invertebrates to vertebrates 4–8 , we hypothesized that a similar mechanism of action underlies its effects in mammalian neurons. To this end, we performed Western blot (WB) analysis and subcellular fractionation on protein samples from mouse brain tissue.…”

Section: Resultsmentioning

confidence: 99%

Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

Getz

Visser

et al. 2017

Sci Rep

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In the central nervous system (CNS), cholinergic transmission induces synaptic plasticity that is required for learning and memory. However, our understanding of the development and maintenance of cholinergic circuits is limited, as the factors regulating the expression and clustering of neuronal nicotinic acetylcholine receptors (nAChRs) remain poorly defined. Recent studies from our group have implicated calpain-dependent proteolytic fragments of menin, the product of the MEN1 tumor suppressor gene, in coordinating the transcription and synaptic clustering of nAChRs in invertebrate central neurons. Here, we sought to determine whether an analogous cholinergic mechanism underlies menin’s synaptogenic function in the vertebrate CNS. Our data from mouse primary hippocampal cultures demonstrate that menin and its calpain-dependent C-terminal fragment (C-menin) regulate the subunit-specific transcription and synaptic clustering of neuronal nAChRs, respectively. MEN1 knockdown decreased nAChR α5 subunit expression, the clustering of α7 subunit-containing nAChRs at glutamatergic presynaptic terminals, and nicotine-induced presynaptic facilitation. Moreover, the number and function of glutamatergic synapses was unaffected by MEN1 knockdown, indicating that the synaptogenic actions of menin are specific to cholinergic regulation. Taken together, our results suggest that the influence of menin on synapse formation and synaptic plasticity occur via modulation of nAChR channel subunit composition and functional clustering.

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Tumor suppressor menin mediates peripheral nerve injury-induced neuropathic pain through potentiating synaptic plasticity

Cited by 15 publications

References 56 publications

Menin: A Tumor Suppressor That Mediates Postsynaptic Receptor Expression and Synaptogenesis between Central Neurons of Lymnaea stagnalis

Menin: A Tumor Suppressor That Mediates Postsynaptic Receptor Expression and Synaptogenesis between Central Neurons of Lymnaea stagnalis

Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica

Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

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