Advancements in Lab-Grown Corticospinal Neurons for ALS and Spinal Injury Research

New evidence demonstrates that corticospinal-like neurons can be generated in vitro with high subtype specificity and fidelity, providing a developmentally informed model for studying amyotrophic lateral sclerosis (ALS) and spinal cord injury.

Corticospinal neurons centrally degenerate in ALS and are the neuronal population whose axons are damaged in spinal cord injury, making accurate reproduction of this subtype essential for relevant disease modeling.

Prior in vitro systems and commonly used differentiation approaches produce broad or mixed cortical projection neuron populations that do not faithfully reproduce corticospinal neuron identity. The study shows that generic Neurog2-driven differentiation yields neurons with aberrant multipolar morphology and mixed molecular signatures, limiting their relevance for disorders characterized by selective corticospinal vulnerability. In contrast, the directed differentiation approach described generates neurons with morphological, molecular, transcriptomic, and electrophysiological features closely resembling corticospinal/subcerebral projection neurons in vivo.

The cultivation strategy is based on developmentally grounded transcriptional control. Investigators identified a subset of endogenous SOX6+/NG2+ cortical progenitors that retain latent neurogenic competence. Using FACS purification and a multi-component transcriptional construct that activates Neurog2 and Fezf2 while antagonizing Olig2, they directed these progenitors toward a cortical output neuron fate. The resulting neurons exhibit unipolar morphology, appropriate axonal architecture, expression of corticospinal-enriched molecular markers, and electrophysiological properties characteristic of functional projection neurons, without adopting features of alternate cortical or subcortical neuronal subtypes.

For ALS research, this work establishes an in vitro system that enables investigation of corticospinal neuron–specific differentiation, identity, and vulnerability—questions that could not be addressed using prior generic cortical neuron models. The system provides a foundation for mechanistic studies and disease modeling focused on the neuronal subtype centrally involved in ALS pathology.

For spinal cord injury research, the ability to generate corticospinal-like neurons with defined identity offers a platform to study properties intrinsic to corticospinal neurons, including axonal morphology and molecular programs relevant to circuit organization.

More broadly, this developmentally based directed differentiation strategy sets a precedent for generating subtype-specific neurons from endogenous cortical progenitors, advancing the fidelity of in vitro models for studying degeneration and repair of defined neuronal circuitry.