Neurexophilin4 is a selectively expressed α-neurexin ligand that modulates specific cerebellar synapses and motor functions.

Xiangling Meng,Joanna Lopez,Szu-Ying Yeh,Junzhan Jing,Roy V Sillitoe,Xiaolong Jiang,Tao Lin,Wei Wang,Christopher M Mcgraw,Amanda M Brown,Huda Y Zoghbi,Wu Chen,Li Wang,Mingshan Xue

doi:10.7554/elife.46773

Xiangling Meng, Joanna Lopez + Show 12 more

Open Access

https://doi.org/10.7554/elife.46773

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Abstract

Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABAARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

Highlights

Transmission of neural activity requires the signaling of numerous molecules, many of which are specific to certain types of neurons or synapses (de Wit and Ghosh, 2016; Missler et al, 2012)
Among the best-studied and most ubiquitous of these synaptic proteins is the family of neurexins, which are presynaptic cell adhesion molecules consisting of both longer a- and shorter b-isoforms with extensive alternative splicing (Rowen et al, 2002)
Because there is no antibody for endogenous Nxph4 currently available, we generated Nxph4-bgeo knock-in mice using targeted embryonic stem cells (ESCs) obtained from the Knock-out Mouse Project (KOMP) repository (Austin et al, 2004) to study Nxph4 expression

Summary

Introduction

Transmission of neural activity requires the signaling of numerous molecules, many of which are specific to certain types of neurons or synapses (de Wit and Ghosh, 2016; Missler et al, 2012). Among the best-studied and most ubiquitous of these synaptic proteins is the family of neurexins, which are presynaptic cell adhesion molecules consisting of both longer a- and shorter b-isoforms with extensive alternative splicing (Rowen et al, 2002) They are proposed to organize synapses throughout the brain (Sudhof, 2008; Sudhof, 2017; Ullrich et al, 1995) by interacting with trans-synaptic binding partners such as neuroligins (Nlgns) (Ichtchenko et al, 1995), neurexophilins (Nxphs) (Missler et al, 1998), leucine-rich repeat transmembrane proteins (LRRTMs) (de Wit et al, 2009; Ko et al, 2009), and Cbln (Matsuda et al, 2010; Uemura et al, 2010). Deletion of Nxph impairs inhibitory control over cerebellar granule cells, possibly contributing to the motor deficits we observed in the Nxph null mice

Results

H S1 S2 Syn β-actin

Discussion

Materials and methods

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