BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons
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Evaluation Summary:
Overall, these authors show that BDNF at the axon terminal can be retrogradely transported to promote new protein synthesis in the neuronal cell body and regulate dendritic morphology, which requires activated TrkB, Akt and mTOR in the soma and nuclear phospho-CREB. Although target-derived neurotrophin effects are well-established in the peripheral nervous system, this mechanism of signaling is less well-understood in the CNS. The manuscript presents a comprehensive analysis of the retrograde transport of BDNF/TrkB from the axon terminal to regulate dendritic morphology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
Brain-derived neurotrophic factor (BDNF) and its receptors tropomyosin kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the CNS. After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.
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Evaluation Summary:
Overall, these authors show that BDNF at the axon terminal can be retrogradely transported to promote new protein synthesis in the neuronal cell body and regulate dendritic morphology, which requires activated TrkB, Akt and mTOR in the soma and nuclear phospho-CREB. Although target-derived neurotrophin effects are well-established in the peripheral nervous system, this mechanism of signaling is less well-understood in the CNS. The manuscript presents a comprehensive analysis of the retrograde transport of BDNF/TrkB from the axon terminal to regulate dendritic morphology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the …
Evaluation Summary:
Overall, these authors show that BDNF at the axon terminal can be retrogradely transported to promote new protein synthesis in the neuronal cell body and regulate dendritic morphology, which requires activated TrkB, Akt and mTOR in the soma and nuclear phospho-CREB. Although target-derived neurotrophin effects are well-established in the peripheral nervous system, this mechanism of signaling is less well-understood in the CNS. The manuscript presents a comprehensive analysis of the retrograde transport of BDNF/TrkB from the axon terminal to regulate dendritic morphology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this study by Moya-Alvarado et al. the authors examine whether BDNF acting on distal axons can regulate dendritic growth in the somatodendritic compartment. They demonstrate that TrkB activated in axons is required for dendritic growth and branching and that inhibition of TrkB kinase activity in cell bodies blocks the ability of axonally-applied BDNF to promote growth. This retrograde BDNF growth pathway is PI-3kinase-, mTOR- and CREB-dependent, and increases the level of translation in cell bodies and dendrites. While there are some minor technical problems in some of the experiments, overall this is a well-performed study using compartmentalized cultures of neurons from transgenic mice, a technically difficult model. The main limitation of this manuscript lies in the fact that all of these results have …
Reviewer #1 (Public Review):
In this study by Moya-Alvarado et al. the authors examine whether BDNF acting on distal axons can regulate dendritic growth in the somatodendritic compartment. They demonstrate that TrkB activated in axons is required for dendritic growth and branching and that inhibition of TrkB kinase activity in cell bodies blocks the ability of axonally-applied BDNF to promote growth. This retrograde BDNF growth pathway is PI-3kinase-, mTOR- and CREB-dependent, and increases the level of translation in cell bodies and dendrites. While there are some minor technical problems in some of the experiments, overall this is a well-performed study using compartmentalized cultures of neurons from transgenic mice, a technically difficult model. The main limitation of this manuscript lies in the fact that all of these results have already been determined in other published studies on BDNF-TrkB signaling, or NGF-TrkA signaling in peripheral neurons. Therefore, while this is the first time all of these results have been presented in a single study, from TrkB in axons all the way to the dendrites, it represents an incremental advancement rather than a significant manuscript for the field. It would have been more surprising if they had obtained opposite results, in fact.
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Reviewer #2 (Public Review):
The study is based on a cutting-edge microfluidics system in combination with neurons from genetically modified animals. Overall, the results are clear, well-controlled and of high quality.
Several comments:
Fig 1/ S1 the authors should consider incorporating it into Fig1, as the data is highly important to the understating of the experimental system that is used throughout the paper.
Most of the studies in the paper are based on pharmacological inhibitors, although this is a powerful approach that allows axonal vs cell body inhibition, off-target effects of these drugs should be considered.
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Reviewer #3 (Public Review):
The manuscript presents the results from compartmentalized cortical cultures to follow the retrograde transport of BDNF/TrkB from the exon terminal to regulate dendritic morphology. In addition to the in vitro experiments using microfluidic chambers, they demonstrate in vivo using a dominant-negative CREB expressed in cortical euros reduced soma size and dendritic branching, Several studies have shown in peripheral neurons that NGF induces local synthesis of CREB, which is then retrogradely transported. In these cortical neurons, it is unclear if the CREB is present in the endosome with the BDNF-TrkB, or whether it is only phosphorylated when the endosome reaches the soma. Phosphorylation may be lost if the TrkB was inactivated in the soma, even if the CREB has been previously phosphorylated in the endosome.
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