Caldendrin and myosin V regulate synaptic spine apparatus localization via ER stabilization in dendritic spines

Anja Konietzny, Jasper Grendel, Alan Kadek, Michael Bucher, Yuhao Han, Nathalie Hertrich, Dick H.W. Dekkers, Jeroen A.A. Demmers, Kay Grünewald, Charlotte Uetrecht, Marina Mikhaylova*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)
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Abstract

Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in structural and molecular diversity of dendritic spines. Active spines with large calcium ion (Ca2+) transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into spines via the actin-based motor myosin V. An increase in synaptic strength correlates with stable anchoring of the ER, followed by the formation of an organelle referred to as the spine apparatus. Here, we show that myosin V binds the Ca2+ sensor caldendrin, a brain-specific homolog of the well-known myosin V interactor calmodulin. While calmodulin is an essential activator of myosin V motor function, we found that caldendrin acts as an inhibitor of processive myosin V movement. In mouse and rat hippocampal neurons, caldendrin regulates spine apparatus localization to a subset of dendritic spines through a myosin V-dependent pathway. We propose that caldendrin transforms myosin into a stationary F-actin tether that enables the localization of ER tubules and formation of the spine apparatus in dendritic spines.

Original languageEnglish
Article numbere106523
JournalEMBO Journal
Volume41
Issue number4
DOIs
Publication statusPublished - 15 Feb 2022

Bibliographical note

Funding Information:
The authors thank W. Wagner (), T.G. Oertner (), and L. Kapitein and C. Hoogenraad () for sharing plasmids. jGCaMP7s was a gift from D. Kim (). They further thank S. Hochmuth for preparing mouse neuronal cultures, J. Bär and M. Andres‐Alonso for preparing rat neuronal cultures, R. Raman for providing the purified caldendrin Ca‐binding mutant protein, the UKE Microscopy Imaging Facility (UMIF) and the Leibniz‐Institut for Neurobiology Magdeburg (LIN) for access and use of their spinning disc and confocal microscopes, Prof. A. Itzen for help with purification of the caldendrin protein, and Dr. I. Hermans‐Borgmeyer for help with the caldendrin knockout mouse line. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Emmy Noether Programme MI1923/1‐2, FOR2419 TP2, SFB877 B12 and Excellence Strategy – EXC‐2049–390688087) and Hertie Network of Excellence in Clinical Neuroscience and Excellence Strategy Program. The Leibniz Institute for Experimental Virology (HPI) is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit (BMG). AKa gratefully acknowledges a postdoctoral fellowship from the Alexander von Humboldt Foundation. CU acknowledges funding through EU Horizon 2020 ERC StG‐2017 759661 SPOCk'S MS. Open Access funding enabled and organized by Projekt DEAL. GFP‐myo Va fl ER‐tDimer2 KIF17‐GFP‐PEX26, PEX‐mRFP‐FKBP, MyoVb‐GFP‐FRB 1‐547 1‐1090 Addgene #104463 2+

Funding Information:
The authors thank W. Wagner (GFP-myo Va fl), T.G. Oertner (ER-tDimer2), and L. Kapitein and C. Hoogenraad (KIF171-547-GFP-PEX26, PEX-mRFP-FKBP, MyoVb1-1090-GFP-FRB) for sharing plasmids. jGCaMP7s was a gift from D. Kim (Addgene #104463). They further thank S. Hochmuth for preparing mouse neuronal cultures, J. B?r and M. Andres-Alonso for preparing rat neuronal cultures, R. Raman for providing the purified caldendrin Ca2+-binding mutant protein, the UKE Microscopy Imaging Facility (UMIF) and the Leibniz-Institut for Neurobiology Magdeburg (LIN) for access and use of their spinning disc and confocal microscopes, Prof. A. Itzen for help with purification of the caldendrin protein, and Dr. I. Hermans-Borgmeyer for help with the caldendrin knockout mouse line. This work was supported by the Deutsche Forschungsgemeinschaft (DFG Emmy Noether Programme MI1923/1-2, FOR2419 TP2, SFB877 B12 and Excellence Strategy ? EXC-2049?390688087) and Hertie Network of Excellence in Clinical Neuroscience and Excellence Strategy Program. The Leibniz Institute for Experimental Virology (HPI) is supported by the Freie und Hansestadt Hamburg and the Bundesministerium f?r Gesundheit (BMG). AKa gratefully acknowledges a postdoctoral fellowship from the Alexander von Humboldt Foundation. CU acknowledges funding through EU Horizon 2020 ERC StG-2017 759661 SPOCk'S MS. Open Access funding enabled and organized by Projekt DEAL. The authors declare that they have no conflict of interest.

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license

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