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Publications

Journal Article Ppublish 1 citation

PubMed: 41980068 DOI: 10.1126/scisignal.adx6752

Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons.

Sci Signal 19(933):eadx6752

Authors: Jose Norberto S Vargas, Anna-Leigh Brown, Kai Sun, Cathleen Hagemann, Bethany Geary, David Villarroel-Campos, Sam Bryce-Smith, Matteo Zanovello, Madeline Lombardo, Stan Majewski, Andrew Tosolini, Maria Secrier, Matthew J Keuss, Andrea Serio, James N Sleigh, Pietro Fratta, Giampietro Schiavo

Affiliations

  • Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
  • UK Dementia Research Institute, University College London, London NW1 3BT, UK.
  • Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK. UK Dementia Research Institute, University College London, London NW1 3BT, UK.
  • Department of Basic and Clinical Neuroscience, King's College London, London SE5 9RT, UK.
  • UK Dementia Research Institute, King's College London, London NW1 3BT, UK.
  • Francis Crick Institute, London NW1 1AT, UK.
  • MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH Scotland, UK.
  • Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK. Francis Crick Institute, London NW1 1AT, UK.
  • Department of Genetics, Evolution, and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK.

Abstract

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 3 LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i 3 LMNs revealed that BDNF temporally regulated the expression and RNA stability of functionally distinct transcriptional programs that included regeneration-associated gene sets, further enhancing their expression. BDNF also regulated the phosphorylation of multiple proteins involved in cytoskeletal dynamics. In compartmentalized cultures of neurons, in which microfluidic chambers isolate somata from their axons, BDNF-induced regeneration depended on axon-specific activation of the ERK-RSK-S6K kinase pathway. The findings show that extrinsic BDNF signaling coordinates intrinsic axon-regeneration programs and highlight the role of spatially regulated kinase activation in this process.

MeSH

Brain-Derived Neurotrophic Factor, Genes, Neurons, Motor Neurons, Brain, Axons, Signal Transduction, Nerve Growth Factors

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