Dataset Information

IgSF21-interacting protein screen

ABSTRACT: We have recently isolated IgSF21 (IGIS) as a novel synaptic organizer that selectively promotes inhibitory presynaptic differentiation. To isolate IgSF21 receptor that mediates synapse-promoting activity of IgSF21, we performed proteomics-based screen using cultured hippocampal neurons with IgSF21-coated magnet beads.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain, Hippocampal Neuron

DISEASE(S): Disease Free

SUBMITTER: Denis Faubert

LAB HEAD: Hideto Takahashi

PROVIDER: PXD006622 | Pride | 2017-09-04

REPOSITORIES: Pride

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Publications

IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2α.

Tanabe Yuko Y Naito Yusuke Y Vasuta Cristina C Lee Alfred Kihoon AK Soumounou Youssouf Y Linhoff Michael W MW Takahashi Hideto H

Nature communications 20170901 1

Coordinated development of excitatory and inhibitory synapses is essential for higher brain function, and impairment in this development is associated with neuropsychiatric disorders. In contrast to the large body of accumulated evidence regarding excitatory synapse development, little is known about synaptic adhesion and organization mechanisms underlying inhibitory synapse development. Through unbiased expression screens and proteomics, we identified immunoglobulin superfamily member 21 (IgSF2 ...[more]

PMID: 28864826

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Project description:The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and post-synaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. One such complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α regulates GABAergic synapse development in the mouse brain, but the precise molecular mechanisms underlying this activity remain unclear. Here, we reveal that the interaction between presynaptic Nrxn2α and postsynaptic IgSF21 is a high-affinity receptor-ligand interaction and identify a binding interface in the IgSF21-Nrxn2α complex. Despite being expressed in both dendritic and somatic regions, IgSF21 preferentially regulates dendritic GABAergic presynaptic differentiation whereas another canonical Nrxn ligand, neuroligin2 (Nlgn2), regulates primarily perisomatic presynaptic differentiation. To explore mechanisms that could underly this compartment specificity, we targeted multiple signaling pathways pharmacologically while monitoring the synaptogenic activity of IgSF21 and Nlgn2. Interestingly, both IgSF21 and Nlgn2 require c-jun N-terminal kinase (JNK)-mediated signaling, whereas Nlgn2, but not IgSF21, additionally requires CaMKII and Src kinase activity. JNK inhibition diminished de novo presynaptic differentiation without affecting the maintenance of formed synapses. We further found that Nrxn2α knockout brains exhibit altered synaptic JNK activity in a sex-specific fashion, suggesting functional linkage between Nrxns and JNK in vivo. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21 and Nlgn downstream of Nrxn2α. We therefore propose a revised hypothesis that Nrxns act as molecular hubs to specify synaptic properties not only through their multiple extracellular ligands but also through distinct intracellular signaling pathways of these ligands.

Project description:The transmission of the malaria parasite between mosquitoes and mammals requires translational repression to ensure that only the proper proteins are expressed at the right time, while still allowing the parasite to prepare the mRNAs it will need for the next developmental stage. With relatively few known specific transcription factors (ApiAP2 family) that may specifically initiate gene transcription, Plasmodium parasites also regulate the stability and turnover of transcripts to provide more comprehensive gene regulation. The CAF1/CCR4/NOT complex has been shown in model organisms to be important for not only mRNA degradation, but also translational control through its deadenylases CAF1 and CCR4. However, few proteins that impose translational repression in Plasmodium sexual stages are known, and those that are characterized primarily affect female gametocytes. Therefore, we have characterized two deadenylases and have uncovered their roles in transmission. We have identified and characterized CCR4-1, which we show plays a role in activating male gametocytes, stabilizing transcripts in gametocytes, and regulating host-to-vector transmission. We find that when ccr4-1 is genetically deleted, there is a loss in the coordination of male gametocyte activation and a reduction in the ability of the parasite to productively infect the mosquito, which is independent of its effect upon male activation. Comparative RNA-seq shows that the deletion of ccr4-1 affects many transcripts that are translationally repressed in females, are related to male gamete function, and/or are important for early mosquito stage development. In contrast, we found that genetic deletion of the major deadenylase Caf1 is lethal. However, we observed that expression of only the N-terminal Caf1 domain is permissive, yet prevents proper complex assembly and phenocopies the ccr4-1 deletion. We therefore conclude that the general and transmission-specialized deadenylases of the CAF1/CCR4/NOT complex play critical and intertwined roles in parasite growth and transmission.

Dataset Information

IgSF21-interacting protein screen

Publications

IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2α.

Similar Datasets

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