Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization
The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and postsynaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains...
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| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1371145/full |
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| author | Nicolas Chofflet Nicolas Chofflet Yusuke Naito Yusuke Naito Anthony John Pastore Nirmala Padmanabhan Nirmala Padmanabhan Phuong Trang Nguyen Christian Poitras Benjamin Feller Benjamin Feller Nayoung Yi Nayoung Yi Jeremie Van Prooijen Husam Khaled Husam Khaled Benoit Coulombe Benoit Coulombe Steven J. Clapcote Steve Bourgault Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Gabby Rudenko Hideto Takahashi Hideto Takahashi Hideto Takahashi Hideto Takahashi |
| author_facet | Nicolas Chofflet Nicolas Chofflet Yusuke Naito Yusuke Naito Anthony John Pastore Nirmala Padmanabhan Nirmala Padmanabhan Phuong Trang Nguyen Christian Poitras Benjamin Feller Benjamin Feller Nayoung Yi Nayoung Yi Jeremie Van Prooijen Husam Khaled Husam Khaled Benoit Coulombe Benoit Coulombe Steven J. Clapcote Steve Bourgault Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Gabby Rudenko Hideto Takahashi Hideto Takahashi Hideto Takahashi Hideto Takahashi |
| author_sort | Nicolas Chofflet |
| collection | DOAJ |
| description | The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and postsynaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. Here, we focus on a synapse organizing complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α (Nrxn2α) that regulates GABAergic synapse development in the mouse brain. 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), primarily regulates perisomatic presynaptic differentiation. To explore mechanisms that could underlie 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. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21-Nrxn2α and Nlgn2-Nrxn synaptic organizing complexes in vitro. 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. |
| first_indexed | 2024-04-24T21:50:22Z |
| format | Article |
| id | doaj.art-b0e5ea6d61414d33a1c87b6f1bb93555 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-24T21:50:22Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b0e5ea6d61414d33a1c87b6f1bb935552024-03-20T15:02:52ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-03-011710.3389/fnmol.2024.13711451371145Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organizationNicolas Chofflet0Nicolas Chofflet1Yusuke Naito2Yusuke Naito3Anthony John Pastore4Nirmala Padmanabhan5Nirmala Padmanabhan6Phuong Trang Nguyen7Christian Poitras8Benjamin Feller9Benjamin Feller10Nayoung Yi11Nayoung Yi12Jeremie Van Prooijen13Husam Khaled14Husam Khaled15Benoit Coulombe16Benoit Coulombe17Steven J. Clapcote18Steve Bourgault19Tabrez J. Siddiqui20Tabrez J. Siddiqui21Tabrez J. Siddiqui22Tabrez J. Siddiqui23Gabby Rudenko24Hideto Takahashi25Hideto Takahashi26Hideto Takahashi27Hideto Takahashi28Synapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaIntegrated Program in Neuroscience, McGill University, Montreal, QC, CanadaSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaIntegrated Program in Neuroscience, McGill University, Montreal, QC, CanadaDepartment of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, United StatesPrairieNeuro Research Centre, Health Sciences Centre, Kleysen Institute for Advanced Medicine, Winnipeg, MB, CanadaDepartment of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, CanadaQuebec Network for Research on Protein Function, Engineering and Applications (PROTEO), Department of Chemistry, Université du Québec à Montréal, Montreal, QC, CanadaDepartment of Translational Proteomics, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, CanadaSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, CanadaSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, CanadaDepartment of Translational Proteomics, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaDepartment of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC, Canada0School of Biomedical Sciences, University of Leeds, Leeds, United KingdomQuebec Network for Research on Protein Function, Engineering and Applications (PROTEO), Department of Chemistry, Université du Québec à Montréal, Montreal, QC, CanadaPrairieNeuro Research Centre, Health Sciences Centre, Kleysen Institute for Advanced Medicine, Winnipeg, MB, CanadaDepartment of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada1The Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada2Program in Biomedical Engineering, University of Manitoba, Winnipeg, MB, CanadaDepartment of Pharmacology and Toxicology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, United StatesSynapse Development and Plasticity Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, QC, CanadaIntegrated Program in Neuroscience, McGill University, Montreal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, Canada3Division of Experimental Medicine, McGill University, Montreal, QC, CanadaThe prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and postsynaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. Here, we focus on a synapse organizing complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α (Nrxn2α) that regulates GABAergic synapse development in the mouse brain. 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), primarily regulates perisomatic presynaptic differentiation. To explore mechanisms that could underlie 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. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21-Nrxn2α and Nlgn2-Nrxn synaptic organizing complexes in vitro. 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.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1371145/fullGABAergic synapseIgSF21neurexin2αneuroligin2signal transductionc-jun N-terminal kinase |
| spellingShingle | Nicolas Chofflet Nicolas Chofflet Yusuke Naito Yusuke Naito Anthony John Pastore Nirmala Padmanabhan Nirmala Padmanabhan Phuong Trang Nguyen Christian Poitras Benjamin Feller Benjamin Feller Nayoung Yi Nayoung Yi Jeremie Van Prooijen Husam Khaled Husam Khaled Benoit Coulombe Benoit Coulombe Steven J. Clapcote Steve Bourgault Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Tabrez J. Siddiqui Gabby Rudenko Hideto Takahashi Hideto Takahashi Hideto Takahashi Hideto Takahashi Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization Frontiers in Molecular Neuroscience GABAergic synapse IgSF21 neurexin2α neuroligin2 signal transduction c-jun N-terminal kinase |
| title | Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| title_full | Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| title_fullStr | Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| title_full_unstemmed | Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| title_short | Structural and functional characterization of the IgSF21-neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| title_sort | structural and functional characterization of the igsf21 neurexin2α complex and its related signaling pathways in the regulation of inhibitory synapse organization |
| topic | GABAergic synapse IgSF21 neurexin2α neuroligin2 signal transduction c-jun N-terminal kinase |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1371145/full |
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