Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA

While the early transcriptional programs governing motor neuron specification are well-defined, the molecular mechanisms regulating the later stages of maturation—such as precise axonal targeting, terminal arborization, and metabolic adaptation—remain poorly understood. This study investigates the role of the transcription factor Nuclear Factor IA (NFIA) in these postmitotic developmental processes.

Using a CNS-specific conditional knockout mouse model (NFIAcKO), the researchers employed a multi-omic approach, including RNA-seq, ChIP-seq, and ATAC-seq, to define the transcriptional landscape regulated by NFIA in the developing spinal cord. They integrated this data with single-cell RNA-seq to isolate motor neuron-specific effects. Functional validation was performed through immunohistochemistry, axonal tracing in cleared tissue, primary motor neuron cultures, and metabolic assays (ATP production and mitochondrial morphology analysis).

NFIA is expressed in most spinal motor neurons throughout development. Its deletion does not affect initial motor neuron specification or progenitor cell numbers, but it significantly disrupts later developmental events. Specifically, NFIAcKO mice exhibit impaired segregation of lateral motor columns (LMCs) and motor pools, leading to intermingling of distinct neuronal populations. Furthermore, NFIA is essential for terminal axonal branching and neuromuscular junction (NMJ) formation. Crucially, the study reveals that NFIA directly promotes the expression of genes involved in oxidative phosphorylation (OXPHOS). In the absence of NFIA, motor neurons show reduced ATP production and fragmented, dysfunctional mitochondria, suggesting that NFIA coordinates the high energy demands required for axonal growth and synapse formation.

This work identifies NFIA as a multifunctional regulator that bridges transcriptional control with metabolic homeostasis in developing neurons. By demonstrating that NFIA is required for terminal arborization and mitochondrial health, the study provides new insights into how motor circuits are assembled and suggests that NFIA may be a key factor in neurodevelopmental disorders characterized by motor deficits.