Abstract
Synapse formation and plasticity depend on nuclear transcription and site-specific protein targeting, but the molecular mechanisms that coordinate these steps have not been well defined. The MEN1 tumor suppressor gene, which encodes the protein menin, is known to induce synapse formation and plasticity in the CNS. This synaptogenic function has been conserved across evolution, however the underlying molecular mechanisms remain unidentified. Here, using central neurons from the invertebrate Lymnaea stagnalis, we demonstrate that menin coordinates subunit-specific transcriptional regulation and synaptic clustering of nicotinic acetylcholine receptors (nAChR) during neurotrophic factor (NTF)-dependent excitatory synaptogenesis, via two proteolytic fragments generated by calpain cleavage. Whereas menin is largely regarded as a nuclear protein, our data demonstrate a novel cytoplasmic function at central synapses. Furthermore, this study identifies a novel synaptogenic mechanism in which a single gene product coordinates the nuclear transcription and postsynaptic targeting of neurotransmitter receptors through distinct molecular functions of differentially localized proteolytic fragments.
Highlights
Sufficient for in vitro and in situ synapse formation between Lymnaea neurons[8,9]
Our report provides the first evidence for a cytoplasmic function of menin, which was previously thought to be primarily a nuclear protein, in the postsynaptic targeting of excitatory nicotinic acetylcholine receptor (nAChR)
We propose a novel model for excitatory synaptogenesis in which the nuclear transcription and postsynaptic targeting of neurotransmitter receptors is coordinated via differential localization and distinct molecular functions of two proteolytic fragments of a single gene product
Summary
Sufficient for in vitro and in situ synapse formation between Lymnaea neurons[8,9]. Other studies from murine models have demonstrated that menin induces plasticity in the spinal cord dorsal horn to produce neuropathic pain in response to peripheral nerve injury[10,11,12], indicating that the role for MEN1 in CNS synapse formation and plasticity has been conserved across evolution. We took advantage of a MEN1-dependent excitatory cholinergic synapse between Lymnaea CNS neurons to pursue identification of the molecular mechanisms underlying the synaptogenic effect of menin. This study (i) is the first to demonstrate that menin is cleaved by calpain, (ii) characterizes a role for menin in the transcriptional regulation of neuronal nAChR, (iii) identifies a novel cytoplasmic function for menin in mediating cell-cell interactions, and (iv) identifies a novel synaptogenic mechanism in which a single gene product coordinates the nuclear transcription and postsynaptic targeting of neurotransmitter receptors
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