Batsel, E. | Search bioRxiv

bioRxiv2025

Sox11 overexpression restores embryonic pro-growth transcription in mature corticospinal tract neurons

Neurons in the central nervous system (CNS) display a high capacity for axon growth during early development but lose this ability at a pivotal differentiation stage marked by synaptic maturation, circuit integration, and a profound shift in gene transcription. Once mature, most CNS neurons fail to reverse this transcriptional switch after axon injury, fundamentally constraining their intrinsic capacity for axon regeneration. Here, we show with single-nucleus RNA sequencing that forced expression of the transcription factor Sox11 in mature corticospinal tract (CST) neurons produces large-scale and stable changes in gene expression that are highly enriched for growth-relevant processes, and which strongly resemble those of pre-synaptic embryonic stages. Moreover, Sox11 is equally effective when delivered to chronically injured CST neurons. These data reveal the ability of Sox11 to reverse a critical step of neuronal maturation even in otherwise unperturbed neurons, clarifying the transcriptional underpinnings and highlighting the potential of Sox11 to act as a pro-regenerative stimulus.

neuroscience↗

bioRxiv2024

Injury distance limits the transcriptional response to spinal injury

The ability of neurons to sense and respond to damage is fundamental to homeostasis and nervous system repair. For some cell types, notably dorsal root ganglia (DRG) and retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response to axon injury that determines survival and regenerative outcomes. In contrast, the injury response of most supraspinal cell types, whose limited regeneration constrains recovery from spinal injury, is mostly unknown. Here we employed single-nuclei sequencing in mice to profile the transcriptional responses of diverse supraspinal cell types to spinal injury. Surprisingly, thoracic spinal injury triggered only modest changes in gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST neurons also responded minimally to cervical injury but much more strongly to intracortical axotomy, including upregulation of numerous regeneration and apoptosis-related transcripts shared with injured DRG and RGC neurons. Thus, the muted response of CST neuron to spinal injury is linked to the injurys distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate that a central challenge for enhancing regeneration after a spinal injury is the limited sensing of distant injuries and the subsequent modest baseline neuronal response.

neuroscience↗