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

Abstract

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.

miR‐22‐3p enhances the intrinsic regenerative abilities of primary sensory neurons via the CBL/p‐EGFR/p‐STAT3/GAP43/p‐GAP43 axis

“…The downregulation of GAP43 is associated with an EGFR inhibitor treatment and development (S. M. Liu et al, ). EGF and EGFR show neurotrophic and protective functions and promote axon growth and synapse formation (Flynn et al, ; Gibson & Tolbert, ; Hermann et al, ; Iwakura et al, ; Peng et al, ). However, GAP43 is a key protein that regulates the intrinsic neurite regenerative ability of neurons that is expressed at a low level in adult primary sensory neurons (Dubovy, Klusakova, Hradilova‐Svizenska, & Joukal, ; Qiao, Cong, Li, Li, & Li, ).…”

“…However, conventional strategies produce limited relief of sensory dysfunction (Dugan & Sagen, 2015). Thus, the and synapse formation (Flynn et al, 2014;Gibson & Tolbert, 2006;Hermann et al, 2000;Iwakura et al, 2011;Peng et al, 1998).…”

“…Therefore, strategies that enhance the intrinsic regenerative capability after SCI are very important. Epidermal growth factor (EGF) is one of the neurotrophic factors that is widely expressed in the nervous system and secreted by neurons to facilitate nearby axon growth and synapse formation by binding to epidermal growth factor receptor (EGFR; Cohen, Ettinger, Lecht, Lelkes, & Lazarovici, 2014;Flynn, Getz, Visser, Janes, & Syed, 2014). Thus, the EGF/EGFR axis functions in both an intracellular and extracellular manner.…”

Src Family Kinases Play a Role in the Functional Clustering of Central Postsynaptic Nicotinic Acetylcholine Receptors

“…As mentioned above, we have demonstrated that CM serves as an extrinsic source of neurotrophic factors required for the postsynaptic expression of excitatory nAChRs in Lymnaea neurons (Xu et al, 2009;Flynn et al, 2014). To determine if the SrcI-induced perturbation of synapse formation was due to a change in the functional expression of postsynaptic nAChRs, single LPeD1 neurons were plated in CM or CM + SrcI (5 µM) overnight, for 14-18 h (Figure 2).…”

“…We have previously shown that excitatory synapse formation between soma-soma pairs of individually identified L. stagnalis neurons requires an extrinsic source of neurotrophic factors (supplied by CM). More specifically, excitatory synapse formation between the presynaptic neuron VD4 and the postsynaptic neuron LPeD1 relies upon activity-induced calcium influx in LPeD1, activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade, and expression of the transcription factor, Lymnaea menin, which are required for the expression of excitatory nAChRs (Xu et al, 2009;Flynn et al, 2014). Without neurotrophic factors, the nAChR phenotype remains inhibitory by "default" (Xu et al, 2009).…”