A postsynaptic GPR158-PLCXD2 complex controls spine apparatus abundance and dendritic spine maturation

Ben Verpoort; Luísa Amado; Jeroen Vandensteen; Elke Leysen; Dan Dascenco; Joris Vandenbempt; Irma Lemmens; Joris Wauman; Kristel Vennekens; Abril Escamilla-Ayala; Ana Cristina Nogueira Freitas; Thomas Voets; Sebastian Munck; Jan Tavernier; Keimpe Wierda; Joris de Wit

doi:10.1016/j.devcel.2025.04.025

A postsynaptic GPR158-PLCXD2 complex controls spine apparatus abundance and dendritic spine maturation

Dev Cell. 2025 May 16:S1534-5807(25)00263-1. doi: 10.1016/j.devcel.2025.04.025. Online ahead of print.

Authors

Ben Verpoort¹, Luísa Amado¹, Jeroen Vandensteen¹, Elke Leysen¹, Dan Dascenco¹, Joris Vandenbempt¹, Irma Lemmens², Joris Wauman², Kristel Vennekens¹, Abril Escamilla-Ayala³, Ana Cristina Nogueira Freitas⁴, Thomas Voets⁴, Sebastian Munck³, Jan Tavernier², Keimpe Wierda⁵, Joris de Wit⁶

Affiliations

¹ VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven 3000, Belgium.
² VIB-UGent Center for Medical Biotechnology, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent 9000, Belgium.
³ VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven 3000, Belgium; VIB Bioimaging Core Leuven, Center for Brain and Disease Research, Leuven 3000, Belgium.
⁴ VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Cellular and Molecular Medicine, Leuven 3000, Belgium.
⁵ VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven 3000, Belgium; VIB-KU Leuven Center for Brain & Disease Research Technologies, Electrophysiology Unit, Leuven 3000, Belgium.
⁶ VIB-KU Leuven Center for Brain & Disease Research, Leuven 3000, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute, Leuven 3000, Belgium. Electronic address: joris.dewit@kuleuven.be.

PMID: 40393451
DOI: 10.1016/j.devcel.2025.04.025

Abstract

The spine apparatus (SA), an endoplasmic reticulum (ER)-related organelle present in a subset of dendritic spines, plays a key role in postsynaptic development and is implicated in various neurological disorders. The molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the G protein-coupled receptor (GPCR)- GPR158 and a constitutively active phospholipase C (PLC) family member, PLC X-domain containing 2 (PLCXD2), that controls SA abundance. Sparse genetic manipulations of mouse cortical neurons in vivo demonstrate that, in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers structural and functional dendritic spine maturation. Extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control over GPR158 signaling. Together, our findings uncover a direct GPCR-like receptor-to-PLC signaling pathway that bypasses canonical PLC regulation via G proteins. This GPR158-PLCXD2 module regulates SA abundance, essential for proper postsynaptic structure and function.

Keywords: AMPA receptor; ER-PM contact sites; GPCR; dendritic spine; organelle; phospholipase; postsynaptic development; receptor signaling; spine apparatus; synapse.