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Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain

Bekir Altas, Liam P. Tuffy, Annarita Patrizi, Kalina Dimova, Tolga Soykan, Andrea J. Romanowski, Colin D. Robertson, Saovleak N. Khim, Garrett W. Bunce, Mateusz C. Ambrozkiewicz, Oleksandr Yagensky, Dilja Krueger-Burg, Matthieu Hammer, He-Hsuan Hsiao, Pawel R. Laskowski, Lydia Dyck, Marco Sassoè-Pognetto, John J.E. Chua, Henning Urlaub, Olaf Jahn, Nils Brose, View ORCID ProfileAlexandros Poulopoulos
doi: https://doi.org/10.1101/2022.07.23.501257
Bekir Altas
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
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Liam P. Tuffy
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
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Annarita Patrizi
3University of Turin, Department of Neuroscience “Rita Levi Montalcini”, I-10126 Turin, Italy
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Kalina Dimova
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
4Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, Neuroproteomics Group, 37075 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Tolga Soykan
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Andrea J. Romanowski
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
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Colin D. Robertson
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
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Saovleak N. Khim
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
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Garrett W. Bunce
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
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Mateusz C. Ambrozkiewicz
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Oleksandr Yagensky
5Max Planck Institute for Multidisciplinary Sciences, Laboratory of Neurobiology, Research Group Protein Trafficking in Synaptic Development and Function, 37077 Göttingen, Germany
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Dilja Krueger-Burg
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
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Matthieu Hammer
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
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He-Hsuan Hsiao
6Max Planck Institute for Multidisciplinary Sciences, Bioanalytical Mass Spectrometry, 37077 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Pawel R. Laskowski
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Lydia Dyck
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Marco Sassoè-Pognetto
3University of Turin, Department of Neuroscience “Rita Levi Montalcini”, I-10126 Turin, Italy
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John J.E. Chua
5Max Planck Institute for Multidisciplinary Sciences, Laboratory of Neurobiology, Research Group Protein Trafficking in Synaptic Development and Function, 37077 Göttingen, Germany
9German Cancer Research Center (DKFZ), Chica und Heinz Schaller-Stiftung Research Group, 69120 Heidelberg, Germany (An.P.); Smith College, Center for Proteomics, Northampton, MA 01063, USA (K.D.); Leibniz Research Institute for Molecular Pharmacology, Department of Molecular Pharmacology and Cell Biology, 13125 Berlin, Germany (T.S.); University Medical Center Mainz, Institute of Microscopic Anatomy and Neurobiology, 55128 Mainz, Germany (D.K.); Charité University Hospital, Institute of Cell Biology and Neurobiology, 10117 Berlin, Germany (M.C.A.); National Chung Hsing University, Department of Chemistry, 40227 Taichung, Taiwan (H-H.H); ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland (P.R.L.); Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (L.D.); National University of Singapore, Yong Loo Lin School of Medicine, Department of Physiology, LSI Neurobiology Programme, Healthy Longevity Translational Research Program (J.J.E.C.)
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Henning Urlaub
6Max Planck Institute for Multidisciplinary Sciences, Bioanalytical Mass Spectrometry, 37077 Göttingen, Germany
7University Medical Center Göttingen, Institute of Clinical Chemistry, Bioanalytics Group, 37075 Göttingen, Germany
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Olaf Jahn
4Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, Neuroproteomics Group, 37075 Göttingen, Germany
8University Medical Center Göttingen, Department of Psychiatry and Psychotherapy, Translational Neuroproteomics Group, 37075 Göttingen, Germany
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Nils Brose
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
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Alexandros Poulopoulos
1University of Maryland School of Medicine, Department of Pharmacology, Baltimore, MD 21201, USA
2Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Neurobiology, 37075 Göttingen, Germany
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  • ORCID record for Alexandros Poulopoulos
  • For correspondence: apoulopoulos@som.umaryland.edu
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ABSTRACT

Neuroligin-3 is a postsynaptic adhesion molecule involved in development, function, and pathologies of synapses in the brain. It is a genetic cause of autism and a potent component of the tumor microenvironment in gliomas. There are four Neuroligins that operate at distinct synapse types, selectively interacting with presynaptic adhesion and postsynaptic scaffold proteins. We investigated the subcellular localization and scaffold specificities of synaptic Neuroligin-3 and demonstrate an unexpected pattern of localization to excitatory synapses in cortical areas, and inhibitory synapses in subcortical areas. Using phosphoproteomics, we identify Neuroligin-3-specific serine phosphorylation in cortex and hippocampus that obstructs a key binding site for inhibitory synapse scaffolds. Using in utero CRISPR/Cas9 knockout and replacement with phosphomimetic mutants, we demonstrate that phosphorylation at this site determines excitatory versus inhibitory synapse localization of Neuroligin-3 in vivo. Our data reveal a mechanism that differentially regulates the balance of Neuroligin-3 between excitatory and inhibitory synapses, adding to our emerging understanding of their role in the development of brain connectivity and associated pathologies.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 24, 2022.
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Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain
Bekir Altas, Liam P. Tuffy, Annarita Patrizi, Kalina Dimova, Tolga Soykan, Andrea J. Romanowski, Colin D. Robertson, Saovleak N. Khim, Garrett W. Bunce, Mateusz C. Ambrozkiewicz, Oleksandr Yagensky, Dilja Krueger-Burg, Matthieu Hammer, He-Hsuan Hsiao, Pawel R. Laskowski, Lydia Dyck, Marco Sassoè-Pognetto, John J.E. Chua, Henning Urlaub, Olaf Jahn, Nils Brose, Alexandros Poulopoulos
bioRxiv 2022.07.23.501257; doi: https://doi.org/10.1101/2022.07.23.501257
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Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain
Bekir Altas, Liam P. Tuffy, Annarita Patrizi, Kalina Dimova, Tolga Soykan, Andrea J. Romanowski, Colin D. Robertson, Saovleak N. Khim, Garrett W. Bunce, Mateusz C. Ambrozkiewicz, Oleksandr Yagensky, Dilja Krueger-Burg, Matthieu Hammer, He-Hsuan Hsiao, Pawel R. Laskowski, Lydia Dyck, Marco Sassoè-Pognetto, John J.E. Chua, Henning Urlaub, Olaf Jahn, Nils Brose, Alexandros Poulopoulos
bioRxiv 2022.07.23.501257; doi: https://doi.org/10.1101/2022.07.23.501257

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