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

TY - UNPB

T1 - BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

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

PY - 2023/11/6

Y1 - 2023/11/6

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 reveal that brain-derived neurotrophic factor (BDNF) amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human motor neurons. Through metabolic RNA sequencing and phosphoproteomic profiling, we elucidate BDNF signalling and its role in axonal regeneration. We discover that BDNF controls RNA stability and transcriptional programs that converge with regeneration-associated gene (RAG) sets. We further unveil that BDNF governs the phosphorylation of multiple proteins essential for cytoskeletal dynamics, a major determinant of effective nerve regeneration. Using compartmentalized neuronal cultures, we demonstrate that the regeneration driven by BDNF depends on the axon-specific activation of ERK/RSK/S6K kinase pathway. We propose a model in which BDNF augments neuron-intrinsic pathways to drive axonal regeneration in human motor neurons.

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 reveal that brain-derived neurotrophic factor (BDNF) amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human motor neurons. Through metabolic RNA sequencing and phosphoproteomic profiling, we elucidate BDNF signalling and its role in axonal regeneration. We discover that BDNF controls RNA stability and transcriptional programs that converge with regeneration-associated gene (RAG) sets. We further unveil that BDNF governs the phosphorylation of multiple proteins essential for cytoskeletal dynamics, a major determinant of effective nerve regeneration. Using compartmentalized neuronal cultures, we demonstrate that the regeneration driven by BDNF depends on the axon-specific activation of ERK/RSK/S6K kinase pathway. We propose a model in which BDNF augments neuron-intrinsic pathways to drive axonal regeneration in human motor neurons.

U2 - 10.1101/2023.11.06.565775

DO - 10.1101/2023.11.06.565775

M3 - Preprint

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

PB - BioRxiv

ER -