BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

Abstract

SUMMARYAxonal degeneration underlies neuromuscular disorders and neuropathies. Dysregulation of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in the peripheral nervous system has long been established to exacerbate axonopathy. However, the molecular programs controlled by BDNF that facilitate axonal regeneration and transport are not well-understood. Here, we unravel the transcriptomic and phosphorylation landscape shaped by BDNF in human iPSC-derived motor neurons. Using SLAM-Seq, we reveal BDNF stimulation increases global transcription rate in motor neurons and governs gene regulatory networks that converge with those engaged during axonal repair/outgrowth. Phosphoproteomic analyses demonstrate that BDNF remodels the phosphorylation landscape of cytoskeletal-binding proteins, especially of structural microtubule-associated proteins. Importantly, the localized axonal-specific activation of ERK1/2 is necessary for BDNF to enhance axonal transport of neurotrophin-containing signaling endosomes and to potentiate axonal regeneration after axotomy. Collectively, this work unveils a novel molecular paradigm that positions BDNF as a core regulator of transcriptional and phosphorylation programs driving axonal regeneration and transport in human motor neurons.HIGHLIGHTSSLAM-seq reveals increased global transcriptional rate by BDNF in human motor neuronsBDNF modulates transcriptional programs that potentiate axonal outgrowth/regenerationBDNF governs the phosphorylation landscape of cytoskeletal-binding proteinsAxonal BDNF-ERK1/2 signaling controls axonal transport and axonal regeneration