Dynein efficiently navigates the dendritic cytoskeleton to drive the retrograde trafficking of BDNF/TrkB signaling endosomes

Ayloo, Swathi; Guedes-Dias, Pedro; Ghiretti, Amy E.; Holzbaur, Erika L.F.

doi:10.1091/mbc.e17-01-0068

Cited by 31 publications

(45 citation statements)

References 42 publications

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“…Synaptopodin puncta in both spines and dendrite shafts were stably anchored at the same locations and sometimes oscillated within areas of 1-2 µm. These data rule out the possibility that clusters of synaptopodin (and thus the SA) might be actively transported via long-distance microtubule-dependent, active transport as it is known for many other membrane organelles (Ayloo et al, 2017;Valenzuela and Perez, 2015;van Spronsen et al, 2013).…”

Section: Synaptopodin Clusters Show No Processive Trafficking and Aresupporting

confidence: 59%

Characterization of neuronal synaptopodin reveals a myosin V-dependent mechanism of synaptopodin clustering at the post-synaptic sites

González-Gallego¹,

Konietzny²,

Pérez-Álvarez³

et al. 2019

Preprint

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STATEMENTHere we demonstrate that the spine apparatus is assembled locally in dendrites. This process, which relies on the presence of synaptopodin and F-actin, is disrupted by interfering with myosin-V activity. ABSTRACTThe spine apparatus (SA) is an endoplasmic reticulum-related organelle which is present in a subset of dendritic spines in cortical and pyramidal neurons. The synaptopodin protein localizes between the stacks of the spine apparatus and is essential for the formation of this unique organelle. Although several studies have demonstrated the significance of the SA and synaptopodin in calcium homeostasis and plasticity of dendritic spines, it is still unclear what factors contribute to its stability at the synapse and whether the SA is locally formed or it is actively delivered to the spines. In this study we show that synaptopodin clusters are stable at their locations. We found no evidence of active microtubule-based transport for synaptopodin. Instead new clusters were emerging in the spines, which we interpret as the SA being assembled on-site.Furthermore, using super-resolution microscopy we show a tight association of synaptopodin with actin filaments. We identify the actin-based motor proteins myosin V and VI as novel interaction partners of synaptopodin and demonstrate that myosin V is important for the formation and/or maintenance of the SA.

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Section: Synaptopodin Clusters Show No Processive Trafficking and Aresupporting

confidence: 59%

Characterization of neuronal synaptopodin reveals a myosin V-dependent mechanism of synaptopodin clustering at the post-synaptic sites

González-Gallego¹,

Konietzny²,

Pérez-Álvarez³

et al. 2019

Preprint

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“…In spite of the change in growth rate, these findings suggest that the microtubule cytoskeleton is not responsible for the changes in velocity. This possibility is supported by a previous study in which treatment of neurons with a low dose of nocodazole, a potent microtubule depolymerization agent, altered the levels of tyrosinated a-tubulin, but did not lead to changes in the cellular trafficking of BDNF-containing vesicles [50].…”

Section: Of 16mentioning

confidence: 53%

IGF 1R regulates retrograde axonal transport of signalling endosomes in motor neurons

et al. 2020

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Signalling endosomes are essential for trafficking of activated ligand–receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, we describe a new modulator of signalling endosome trafficking, the insulin‐like growth factor 1 receptor (IGF1R). We show that IGF1R inhibition increases the velocity of signalling endosomes in motor neuron axons, both in vitro and in vivo. This effect is specific, since IGF1R inhibition does not alter the axonal transport of mitochondria or lysosomes. Our results suggest that this change in trafficking is linked to the dynein adaptor bicaudal D1 (BICD1), as IGF1R inhibition results in an increase in the de novo synthesis of BICD1 in the axon of motor neurons. Finally, we found that IGF1R inhibition can improve the deficits in signalling endosome transport observed in a mouse model of amyotrophic lateral sclerosis (ALS). Taken together, these findings suggest that IGF1R inhibition may be a new therapeutic target for ALS.

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“…Microtubule plus tip dynamics and microtubule stability affect cargo trafficking along neuronal dendrites (Tas et al , ). Microtubule‐based trafficking of cargo such as TrkB is important for neuronal function (Zweifel et al , ), and in dendrites, it is dependent on minus‐end directed dynein and plus‐end directed kinesin (Hirokawa et al , ; Ayloo et al , ). Therefore, we decided to analyse dendritic transport of BDNF/TrkB, a well‐studied cargo for microtubule‐based transport, and tested if trafficking of BDNF/TrkB carrying endosomal vesicles was affected in CDKL5 KO neurons.…”

Section: Resultsmentioning

confidence: 99%

Chemical genetic identification of CDKL 5 substrates reveals its role in neuronal microtubule dynamics

et al. 2018

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Loss‐of‐function mutations in CDKL5 kinase cause severe neurodevelopmental delay and early‐onset seizures. Identification of CDKL5 substrates is key to understanding its function. Using chemical genetics, we found that CDKL5 phosphorylates three microtubule‐associated proteins: MAP1S, EB2 and ARHGEF2, and determined the phosphorylation sites. Substrate phosphorylations are greatly reduced in CDKL5 knockout mice, verifying these as physiological substrates. In CDKL5 knockout mouse neurons, dendritic microtubules have longer EB3‐labelled plus‐end growth duration and these altered dynamics are rescued by reduction of MAP1S levels through shRNA expression, indicating that CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S. We show that phosphorylation by CDKL5 is required for MAP1S dissociation from microtubules. Additionally, anterograde cargo trafficking is compromised in CDKL5 knockout mouse dendrites. Finally, EB2 phosphorylation is reduced in patient‐derived human neurons. Our results reveal a novel activity‐dependent molecular pathway in dendritic microtubule regulation and suggest a pathological mechanism which may contribute to CDKL5 deficiency disorder.

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Dynein efficiently navigates the dendritic cytoskeleton to drive the retrograde trafficking of BDNF/TrkB signaling endosomes

Cited by 31 publications

References 42 publications

Characterization of neuronal synaptopodin reveals a myosin V-dependent mechanism of synaptopodin clustering at the post-synaptic sites

Characterization of neuronal synaptopodin reveals a myosin V-dependent mechanism of synaptopodin clustering at the post-synaptic sites

IGF 1R regulates retrograde axonal transport of signalling endosomes in motor neurons

Chemical genetic identification of CDKL 5 substrates reveals its role in neuronal microtubule dynamics

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