Rab5 and Rab4 Regulate Axon Elongation in the<i>Xenopus</i>Visual System

Falk, Julien; Konopacki, Filip A.; Zivraj, Krishna H.; Holt, Christine E.

doi:10.1523/jneurosci.0876-13.2014

Cited by 50 publications

(59 citation statements)

References 134 publications

(21 reference statements)

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“…Thus, it is conceivable that at least in part the altered processes are caused by disturbed long-distance transport. This is supported by recent findings studying axon elongation, where Rab5-mediated control of endosome trafficking is important for axon growth [70] and ESCRT-II transports mRNAs to regulate local protein synthesis [71]. In summary, our findings not only have implications for fungal biology but also provide new inspiration for neuronal research.…”

Section: Resultssupporting

confidence: 84%

The ESCRT regulator Did2 maintains the balance between long-distance endosomal transport and endocytic trafficking

2017

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In highly polarised cells, like fungal hyphae, early endosomes function in both endocytosis as well as long-distance transport of various cargo including mRNA and protein complexes. However, knowledge on the crosstalk between these seemingly different trafficking processes is scarce. Here, we demonstrate that the ESCRT regulator Did2 coordinates endosomal transport in fungal hyphae of Ustilago maydis. Loss of Did2 results in defective vacuolar targeting, less processive long-distance transport and abnormal shuttling of early endosomes. Importantly, the late endosomal protein Rab7 and vacuolar protease Prc1 exhibit increased shuttling on these aberrant endosomes suggesting defects in endosomal maturation and identity. Consistently, molecular motors fail to attach efficiently explaining the disturbed processive movement. Furthermore, the endosomal mRNP linker protein Upa1 is hardly present on endosomes resulting in defects in long-distance mRNA transport. In conclusion, the ESCRT regulator Did2 coordinates precise maturation of endosomes and thus provides the correct membrane identity for efficient endosomal long-distance transport.

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Section: Resultssupporting

confidence: 84%

The ESCRT regulator Did2 maintains the balance between long-distance endosomal transport and endocytic trafficking

2017

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“…Rab4 activity is essential for many neuronal processes such as the extension of axonal growth cone in Xenopus and maintenance of the dendritic spines in rat hippocampal cells (Brown et al, 2007; Falk et al, 2014). Also, elevated levels of Rab4 have been correlated with the endosomal abnormalities in the cholinergic basal forebrain of patients who have the Alzheimer’s disease (Cataldo et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

“…The activity of Rab4 is critical for the physiology of the neuron-like extension of the growth cone (Falk et al, 2014). Overexpressed levels and activity of Rab4 found in conjunction with neuropathy, such as the Alzheimer’s disease, suggest that overactivation of the endosomal system could influence the disease progression (Cataldo et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Recruitment of Rab4 on sorting intermediate endosomes allows the transfer of vesicular cargoes from early endosomes to recycling endosomes in axons and at synapses (de Renzis et al, 2002; Hoogenraad et al, 2010; Jovic et al, 2010). The activity of Rab4 has also been implicated in the progression of growth cone in Xenopus , and the maintenance of dendritic spines in rat hippocampal neurons (Brown et al, 2007; Falk et al, 2014). Furthermore, endosomal abnormalities found in the cholinergic basal forebrain of patients with Alzheimer disease correlate with elevated levels of Rab4 (Cataldo et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Anterograde Transport of Rab4-Associated Vesicles Regulates Synapse Organization in Drosophila

2017

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Summary Local endosomal recycling at synapses is essential to maintain neurotransmission. Rab4GTPase, found on sorting endosomes, is proposed to balance the flow of vesicles between endocytic, recycling and degradative pathways in the presynaptic compartment. Here, we report that Rab4-associated vesicles move bidirectionally in Drosophila axons but with an anterograde bias, resulting in their moderate enrichment at the synaptic region of the larval ventral ganglion. Results from FRB-FKBP conjugation assays in rat embryonic fibroblasts together with genetic analyses in Drosophila indicate that an association with Kinesin-2 (mediated by the tail domain of Kinesin-2α/KIF3A/KLP64D subunit) moves Rab4-associated vesicles towards the synapse. Reduction in the anterograde traffic of Rab4 causes an expansion of the volume of the synapse-bearing region in the ventral ganglion and increases the motility of Drosophila larvae. These results suggest that Rab4-dependent vesicular traffic towards the synapse plays a vital role in maintaining synaptic balance in this neuronal network.

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“…Germane to Rab4, it is known to regulate (I) constitutive endocytosis of dopamine D2 receptors in striatal medium spiny neurons (Li et al, 2012), (II) is critical for the maintenance of dendritic spine size in rat hippocampus (Brown et al, 2007), (III) promotes elongation/growth of developing Xenopus retinal axons (Falk et al, 2014), (IV) is a key binding partner of GRIP-associated protein-1 (GRASP-1) which facilitates AMPA receptor recycling in primary hippocampal neurons (Hoogenraad et al, 2010), and (V) is activated by acute stress and promotes NMDAR/AMPAR glutamatergic neurotransmission which enhances working memory in rodents (Yuen et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Whole-transcriptome microarray analysis reveals regulation of Rab4 by RBM5 in neurons

2017

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RNA binding motif 5 (RBM5) is a nuclear protein that modulates gene transcription and mRNA splicing in cancer cells. The brain is among the highest RBM5 expressing organ in the body but its mRNA target(s) or functions in the CNS have not been elucidated. Here we knocked down (KO) RBM5 in primary rat cortical neurons and analyzed total RNA extracts by gene microarray vs. neurons transduced with lentivirus to deliver control (non-targeting) shRNA. The mRNA levels of Sec23A (involved in ER-Golgi transport) and the small GTPase Rab4a (involved in endocytosis/protein trafficking) were increased in RBM5 KO neurons relative to controls. At the protein level, only Rab4a was significantly increased in RBM5 KO extracts. Also, elevated Rab4a levels in KO neurons were associated with decreased membrane levels of oligomeric serotonin transporters (SERT). Finally, RBM5 KO was associated with increased uptake of membrane-derived monomeric SERT. Significance: Rab4a is involved in the regulation of endocytosis and protein trafficking in cells. In the CNS it regulates diverse neurobiological functions including (but not limited to) trafficking of transmembrane proteins involved in neurotransmission (e.g. SERT), maintaining dendritic spine size, promoting axonal growth, and modulates cognition. Our findings suggest that RBM5 regulates Rab4a in rat neurons.

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Rab5 and Rab4 Regulate Axon Elongation in theXenopusVisual System

Cited by 50 publications

References 134 publications

The ESCRT regulator Did2 maintains the balance between long-distance endosomal transport and endocytic trafficking

The ESCRT regulator Did2 maintains the balance between long-distance endosomal transport and endocytic trafficking

Anterograde Transport of Rab4-Associated Vesicles Regulates Synapse Organization in Drosophila

Whole-transcriptome microarray analysis reveals regulation of Rab4 by RBM5 in neurons

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