# Qki5 safeguards spinal motor neuron function by defining the motor neuron-specific transcriptome via pre-mRNA processing

## TL;DR

The protein Qki5 helps maintain motor neurons by regulating RNA to create a unique transcriptome, and its dysfunction may lead to motor neuron diseases.

## Contribution

Qki5 is identified as a key RNA-binding protein that defines the motor neuron-specific transcriptome and safeguards motor neuron function.

## Key findings

- Qki5 is predominantly expressed in motor neurons and regulates their specific transcriptome through pre-mRNA splicing.
- Loss of Qki5 leads to motor neuron degeneration and activation of stress pathways like JNK/SAPK.
- Qki5-dependent RNA regulation is crucial for maintaining mature motor neurons and preventing neurodegeneration.

## Abstract

RNA-binding proteins (RBPs) play pivotal roles in a cellular RNA metabolism by regulating multiple steps of the posttranscriptional gene regulation and its functional abnormality is linked to pathogenesis of various diseases. Most of RBPs are widely expressed across tissues and this would suggest a role of supporting a basic cellular function. On the other hand, the molecular mechanisms underlying cell type-specific transcriptome and molecular features related to the selective cell vulnerability remain to be elucidated. Here, we describe a role of Quaking5 (Qki5) in the generation of the motor neuron (MN)-specific transcriptome profile through pre-messenger ribonucleic acid (mRNA) regulation. Moreover, Qki5 contributes to the maintenance of MNs, and its dysfunction is associated with MN vulnerability.

Many RNA-binding proteins (RBPs) are linked to the dysregulation of RNA metabolism in motor neuron diseases (MNDs). However, the molecular mechanisms underlying MN vulnerability have yet to be elucidated. Here, we found that such an RBP, Quaking5 (Qki5), contributes to formation of the MN-specific transcriptome profile, termed “MN-ness,” through the posttranscriptional network and maintenance of the mature MNs. Immunohistochemical analysis and single-cell RNA sequencing (scRNA-seq) revealed that Qki5 is predominantly expressed in MNs, but not in other neuronal populations of the spinal cord. Furthermore, comprehensive RNA sequencing (RNA-seq) analyses revealed that Qki5-dependent RNA regulation plays a pivotal role in generating the MN-specific transcriptome through pre-messenger ribonucleic acid (mRNA) splicing for the synapse-related molecules and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathways. Indeed, MN-specific ablation of the Qki5 caused neurodegeneration in postnatal mice and loss of Qki5 function resulted in the aberrant activation of stress-responsive JNK/SAPK pathway both in vitro and in vivo. These data suggested that Qki5 plays a crucial biological role in RNA regulation and safeguarding of MNs and might be associated with pathogenesis of MNDs.