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

TY - JOUR

T1 - Brain-derived neurotrophic factor coordinates neuron-intrinsic programs to enhance axonal regeneration in human motor neurons

AU - Vargas, Jose Norberto S.

AU - Brown, Anna Leigh

AU - Sun, Kai

AU - Hagemann, Cathleen

AU - Geary, Bethany

AU - Villarroel-Campos, David

AU - Bryce-Smith, Sam

AU - Zanovello, Matteo

AU - Lombardo, Madeline

AU - Majewski, Stan

AU - Tosolini, Andrew

AU - Secrier, Maria

AU - Keuss, Matthew J.

AU - Serio, Andrea

AU - Sleigh, James N.

AU - Fratta, Pietro

AU - Schiavo, Giampietro

N1 - Publisher Copyright: © 2026 The Authors.

PY - 2026/4/14

Y1 - 2026/4/14

N2 - 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 neuronintrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i3 LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i3 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.

AB - 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 neuronintrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i3 LMNs). Metabolic RNA sequencing (SLAM-seq) and phosphoproteomic profiling of i3 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.

UR - https://www.scopus.com/pages/publications/105035819626

U2 - 10.1126/scisignal.adx6752

DO - 10.1126/scisignal.adx6752

M3 - Article

C2 - 41980068

AN - SCOPUS:105035819626

SN - 1945-0877

VL - 19

JO - Science Signaling

JF - Science Signaling

IS - 933

M1 - eadx6752

ER -