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The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i Show less

Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture. Show less