BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as, Ginny G.; Guardia, Carlos M.; Pace, Raffaella De; Britt, Dylan; Bonifacino, Juan S.

doi:10.1073/pnas.1616363114

Cited by 185 publications

(257 citation statements)

References 78 publications

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“…71.4% of MB‐positive moving puncta were co‐transported with CD63‐eGFP‐labeled vesicle‐like focal puncta, and an equal percentage of these moved anterogradely and retrogradely (Fig B–D, F and G, and Movies EV3 and EV4). This bidirectional transport is consistent with previously published studies on LE/Ly trafficking in embryonic neurons (Farías et al , ). Similar results were obtained when growth cones were cultured from older embryos (Appendix Fig S2A–G and Movie EV5).…”

Section: Resultssupporting

confidence: 93%

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

et al. 2020

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Various species of non‐coding RNAs (ncRNAs) are enriched in specific subcellular compartments, but the mechanisms orchestrating their localization and their local functions remain largely unknown. We investigated both aspects using the elongating retinal ganglion cell axon and its tip, the growth cone, as models. We reveal that specific endogenous precursor microRNAs (pre‐miRNAs) are actively trafficked to distal axons by hitchhiking primarily on late endosomes/lysosomes. Upon exposure to the axon guidance cue semaphorin 3A (Sema3A), pre‐miRNAs are processed specifically within axons into newly generated miRNAs, one of which, in turn, silences the basal translation of tubulin beta 3 class III (TUBB3), but not amyloid beta precursor protein (APP). At the organismal level, these mature miRNAs are required for growth cone steering and a fully functional visual system. Overall, our results uncover a novel mode of ncRNA transport from one cytosolic compartment to another within polarized cells. They also reveal that newly generated miRNAs are critical components of a ncRNA‐based signaling pathway that transduces environmental signals into the structural remodeling of subcellular compartments.

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Section: Resultssupporting

confidence: 93%

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

et al. 2020

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“…Lysosomes are associated with different types of MT motors (kinesin‐1, kinesin‐2, dynein) (Pu et al , ; Farias et al , ), which makes it difficult to discriminate which motor might be primarily affected by the F‐actin mesh, or if the presence of actin patches triggers competition between these motor proteins, a so‐called “tug of war”, resulting in stops and switches in transport directionality (Hancock, ). In order to be able to rule out tug‐of‐war effects, we decided to engineer a cargo that is only transported by one type of dendritic MT motor.…”

Section: Resultsmentioning

confidence: 99%

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

et al. 2019

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Organelle positioning within neurites is required for proper neuronal function. In dendrites, with their complex cytoskeletal organization, transport of organelles is guided by local specializations of the microtubule and actin cytoskeleton, and by coordinated activity of different motor proteins. Here, we focus on the actin cytoskeleton in the dendritic shaft and describe dense structures consisting of longitudinal and branched actin filaments. These actin patches are devoid of microtubules and are frequently located at the base of spines, or form an actin mesh around excitatory shaft synapses. Using lysosomes as an example, we demonstrate that the presence of actin patches has a strong impact on dendritic organelle transport, as lysosomes frequently stall at these locations. We provide mechanistic insights on this pausing behavior, demonstrating that actin patches form a physical barrier for kinesin‐driven cargo. In addition, we identify myosin Va as an active tether which mediates long‐term stalling. This correlation between the presence of actin meshes and halting of organelles could be a generalized principle by which synapses control organelle trafficking.

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“…The GTP form of ARL8B binds to SKIP to recruit KIF5 onto the lysosomal membrane. Although a recent study has shown that this complex is essential for the axonal transport of lysosomes [35], we could not analyze the role of BORC in this phenomena in this study as mature lysosomes are largely absent in DA9 axons (Figure S1B). …”

Section: Discussionmentioning

confidence: 96%

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

Niwa

et al. 2017

Current Biology

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Summary Axonal transport of synaptic vesicle precursors (SVPs) is essential for synapse development and function. The conserved ARF-like small GTPase ARL-8 is localized to SVPs and directly activates UNC-104/KIF1A, the axonal-transport kinesin for SVPs in C. elegans. It is not clear how ARL-8 is activated in this process. Here we show that part of the BLOC-1 related complex (BORC), previously shown to regulate lysosomal transport, is required to recruit and activate ARL-8 on SVPs. We found mutations in six BORC subunits-- blos-1/BLOS1, blos-2/BLOS2, snpn-1/Snapin, sam-4/Myrlysin, blos-7/Lyspersin and blos-9/MEF2BNB cause defects in axonal transport of SVPs, leading to ectopic accumulation of synaptic vesicles in the proximal axon. This phenotype is suppressed by constitutively active arl-8 or unc-104 mutants. Furthermore, SAM-4/Myrlysin, a subunit of BORC, promotes the GDP to GTP exchange of ARL-8 in vitro and recruits ARL-8 onto SVPs in vivo. Thus, BORC regulates the axonal transport of synaptic materials and synapse formation by controlling the nucleotide state of ARL-8. Interestingly, the other two subunits of BORC essential for lysosomal transport, kxd-1/KXD1 and blos-8/Diaskedin, are not required for the SVP transport, suggesting distinct subunit requirements for lysosomal and SVP trafficking.

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BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Cited by 185 publications

References 78 publications

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

Axonal precursor mi RNA s hitchhike on endosomes and locally regulate the development of neural circuits

F‐actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8

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