Biology subjects

Gautier, O.

Publications and source records attributed to Gautier, O..

4 recordsLinked to original sources

bioRxiv2026

A consensus spinal cord cell type atlas across mouse, macaque, and human

The spinal cord contains evolutionarily conserved cell types critical for motor function, sensory processing, and autonomic regulation, many of which are implicated in diverse neurological diseases and injuries. Yet the field lacks a comprehensive molecular characterization of cellular diversity in human, macaque, and mouse spinal cord. Here, we present a unified, cross-species cell type atlas based on the integration of single-nucleus gene expression, chromatin accessibility, and spatial transcriptomic data from segments within cervical, thoracic, lumbar, and sacral regions, including motor neurons (MNs) sampled across the entire rostro-caudal axis of the macaque spinal cord. Leveraging the spatial distributions of our molecularly defined cell types, we generated a cell type-guided anatomical map of spinal cord laminae and nuclei. We identified both conserved and species-specific cellular features, including gene expression patterns across distinct MN subtypes in the primate spinal cord. Cross-species cis-regulatory analysis and deep learning sequence models dissected the enhancer logic underlying viral targeting, uncovering conserved transcription factor grammar encoding cellular identity. Together, these results establish a unifying molecular and anatomical taxonomy of spinal cord cell types across species.

neuroscience↗

bioRxiv2025

An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS

To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named disease-associated motor neurons (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.

neuroscience↗

bioRxiv2025

KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

neuroscience↗

bioRxiv2023

Human motor neurons are rare and can be transcriptomically divided into known subtypes

We performed single-nucleus RNA-sequencing on adult human spinal cord using a neuronal nuclei enrichment strategy. We obtained transcriptomic profiles of >14,000 spinal neurons, including a small population of motor neurons that shares similarities with mouse motor neurons and can be subdivided into alpha and gamma subtypes. We sought to compare our results to those from a recent study by Yadav and colleagues, which provides a single-nucleus transcriptomic atlas of the human spinal cord. While most neuronal nuclei from both studies share similar features, our results from motor neurons differ substantially. We reanalyzed their RNA-sequencing data and provide evidence that the authors incorrectly identified cholinergic cellular debris as motor neuron nuclei in their dataset, raising doubts about their conclusions regarding motor neurons. Our findings underscore the challenges associated with transcriptionally profiling motor neurons from the spinal cord because of their rarity. We propose specific enrichment strategies and recommend important quality control measures for future transcriptional profiling studies involving human spinal cord tissue and rare cell types.

neuroscience↗