A Tale of Two C-Tails

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Date
2016-02-24
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Johns Hopkins University
Abstract
The processing and integration of information in the brain depends on cell-to-cell communication. Synapses, the sites of communication, are specialized asymmetrical connections between neurons that allow for the efficient transfer of information. Synaptic formation, structure, maturation, and maintenance are sustained by a multifarious network of bidirectional cellular adhesion molecules that span the synaptic cleft, aligning the presynaptic active zone and postsynaptic density. Arguably, the best-characterized synaptic cell adhesion molecules are the presynaptic neurexins and postsynaptic neuroligins. The transsynaptic heterophilic interaction between the extracellular domains of neuroligins and neurexins can induce synapse formation and maturation. Although intensely studied, the signaling pathways that regulate neuroligins ability to generate, maintain, and strengthen functional synapses in the developing and mature brain are largely unknown. The genesis of new synapses by neuroligin has been shown to be dependent on Ca2+/CaM Kinase II, but the mechanism behind this regulation is unknown. Here, we report that Ca2+/CaM Kinase II robustly phosphorylates the intracellular domain of neuroligin-1 on T739 in response to sensory experience in the brain. Blocking phosphorylation drastically decreases neuroligin-1 surface expression, thereby reducing its ability to induce synaptogenesis. Therefore we report that neuroligin is indeed changed by ongoing activity and a direct link between synaptogenesis and calcium in the cell. In humans, alterations that perturb neuroligins are implicated in cognitive disorders, highlighting their critical roles at the synapse. However, the mechanisms by which the majority of these mutations may contribute to the disease are unknown. Here we show that endogenous neuroligin-4X is robustly phosphorylated by protein kinase C at T707. Furthermore, R704C, a well-described autism mutation, completely eliminates T707 phosphorylation. A phospho-mimetic mutation at T707 has a profound effect on neuroligin-4X-mediated excitatory potentiation. Our results now establish an important interplay between a genetic mutation, a key posttranslational modification, and robust synaptic changes, which can provide insights into the synaptic dysfunction of autism spectrum disorders. The extracellular domain of neuroligin-3 promotes glioma growth. Neuroligin-3 expression inversely correlates with survival in human glioblastoma providing a link between neuroligins and cancer. How neuroligin-3 is processed to produce solely its extracellular domain remains an enigma. Here, we report that protein kinase C signaling induces the proteolytic cleavage of full-length neuroligin-3 to produce the extracellular domain. We show that this regulation is isoform and kinase specific. Therefore we report a functional interplay between protein kinase C signaling and neuroligin-3, which may play a role in the etiology of brain cancer. Taken together, these studies described in this thesis contribute to and expand the understanding of the mechanisms governing synaptogenesis. Historically, neuroligins have been viewed as static building blocks of synapses. Our research identifies pathways by which neuroligins are transiently modified and acutely enhance synapses in an activity-dependent manner. The aberrant regulation of neuroligins contributes to disorders ranging from autism spectrum disorders to cancer underlying their importance for continued study.
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Keywords
synaptogenesis, neuroligin, phosphorylation
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