Rab2 regulates presynaptic precursor vesicle biogenesis at the trans-Golgi

Götz, Torsten; Puchkov, Dmytro; Lysiuk, Veronika; Lützkendorf, Janine; Nikonenko, Alexander G.; Quentin, Christine; Lehmann, Martin; Sigrist, Stephan J.; Petzoldt, Astrid G.

doi:10.1083/jcb.202006040

Cited by 20 publications

(21 citation statements)

References 74 publications

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“…In neurons, the biogenesis of SVPs and DCVs involves complex sorting steps, followed by an association between the transport packet and the axonal motor, but how these processes are coordinated is unclear. 15, 58, 59 Particularly in cases where the same motor carries different cargo, specific mechanisms that promote its association with given cargos should exist. KIF1A/UNC-104 has a Pleckstrin Homology domain at its C-terminal tail that has been shown to bind PI(4,5)P2 and PI(4)P and is thought to be the main determinant in cargo recognition.…”

Section: Discussionmentioning

confidence: 99%

End Binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles

Park

Miller

Camilli

et al. 2023

Preprint

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Axonal transport is key to neuronal function. Efficient transport requires specific motor-cargo association in the soma, yet the mechanisms regulating this early step remain poorly understood. We found that EBP-1, the C. elegans ortholog of the canonical microtubule end binding protein EB1, promotes the specific association between kinesin-3/KIF1A/UNC-104 and Dense Core Vesicles (DCVs) prior to their axonal delivery. Using single-neuron, in vivo labelling of endogenous cargo and EBs, we observed reduced axonal abundance and reduced secretion of DCV cargo, but not other KIF1A/UNC-104 cargo, in ebp-1 mutants. This reduction could be traced back to fewer exit events from the cell body, where EBP-1 colocalized with the DCV sorting machinery at the trans Golgi, suggesting that this is the site of EBP-1 function. In addition to its microtubule binding CH domain, mammalian EB1 interacted with mammalian KIF1A in an EBH domain dependent manner, and expression of mammalian EB1 or the EBH domain was sufficient to rescue DCV transport in ebp-1 mutants. Our results suggest a model in which kinesin-3 binding and microtubule binding by EBP-1 cooperate to transiently enrich the motor near sites of DCV biogenesis to promote motor-cargo association. In support of this model, tethering either EBP-1 or a kinesin-3 KIF1A/UNC-104 interacting domain from an unrelated protein to the Golgi restored the axonal abundance of DCV proteins in ebp-1 mutants. These results uncover an unexpected role for a microtubule associated protein and provide insight into how specific kinesin-3 cargo are delivered to the axon.

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Section: Discussionmentioning

confidence: 99%

End Binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles

Park

Miller

Camilli

et al. 2023

Preprint

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“…Rab2 proteins, which are composed of Rab2b and Rab2a, are involved in the regulation of retrograde transport between the ER and the Golgi body [ 21 , 22 , 23 ]. They appear likely to regulate vesicle recycling around the Golgi body and autophagy in neuronal cells [ 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Hesperetin Ameliorates Inhibition of Neuronal and Oligodendroglial Cell Differentiation Phenotypes Induced by Knockdown of Rab2b, an Autism Spectrum Disorder-Associated Gene Product

Kato

Shirai

Ohbuchi

et al. 2023

Neurology International

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Autism spectrum disorder (ASD) is a central nervous system (CNS) neurodevelopmental disorder that includes autism, pervasive developmental disorder, and Asperger’s syndrome. ASD is characterized by repetitive behaviors and social communication deficits. ASD is thought to be a multifactorial disorder with a range of genetic and environmental factors/candidates. Among such factors is the rab2b gene, although it remains unclear how Rab2b itself is related to the CNS neuronal and glial developmental disorganization observed in ASD patients. Rab2 subfamily members regulate intracellular vesicle transport between the endoplasmic reticulum and the Golgi body. To the best of our knowledge, we are the first to report that Rab2b positively regulates neuronal and glial cell morphological differentiation. Knockdown of Rab2b inhibited morphological changes in N1E-115 cells, which are often used as the neuronal cell differentiation model. These changes were accomplished with decreased expression levels of marker proteins in neuronal cells. Similar results were obtained for FBD-102b cells, which are used as the model of oligodendroglial cell morphological differentiation. In contrast, knockdown of Rab2a, which is another Rab2 family member not known to be associated with ASD, affected only oligodendroglial and not neuronal morphological changes. In contrast, treatment with hesperetin, a citrus flavonoid with various cellular protective effects, in cells recovered the defective morphological changes induced by Rab2b knockdown. These results suggest that knockdown of Rab2b inhibits differentiation in neuronal and glial cells and may be associated with pathological cellular phenotypes in ASD and that hesperetin can recover their phenotypes at the in vitro level at least.

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“…The extracellular matrix presented in the GO cellular component analysis of the hippocampus is involved in the regulation of the structure and function of the dendritic spine (Dityatev et al, 2010). Intracellular organelles, for example, the Golgi apparatus, are necessary for the formation of synaptic vesicles and thus play a dual role in synaptogenesis and neurotransmission (Götz et al, 2021). The cellular component analysis of the cerebral cortex revealed that DEGs were mainly involved in pre-and postsynaptic components.…”

Section: Discussionmentioning

confidence: 99%

Conditional deletion of MAD2B in forebrain neurons enhances hippocampus-dependent learning and memory in mice

Su²,

Zhi³

et al. 2022

Front. Cell. Neurosci.

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Mitotic arrest deficient 2-like protein 2 (MAD2B) is not only a DNA damage repair agent but also a cell cycle regulator that is widely expressed in the hippocampus and the cerebral cortex. However, the functions of MAD2B in hippocampal and cerebral cortical neurons are poorly understood. In this study, we crossed MAD2Bflox/flox and calcium/calmodulin-dependent protein kinase II alpha (Camk2a)-Cre mice to conditionally knock out MAD2B in the forebrain pyramidal neurons by the Cre/loxP recombinase system. First, RNA sequencing suggested that the differentially expressed genes in the hippocampus and the cerebral cortex between the WT and the MAD2B cKO mice were related to learning and memory. Then, the results of behavioral tests, including the Morris water maze test, the novel object recognition test, and the contextual fear conditioning experiment, suggested that the learning and memory abilities of the MAD2B cKO mice had improved. Moreover, conditional knockout of MAD2B increased the number of neurons without affecting the number of glial cells in the hippocampal CA1 and the cerebral cortex. At the same time, the number of doublecortin-positive (DCX+) cells was increased in the dentate gyrus (DG) of the MAD2B cKO mice. In addition, as shown by Golgi staining, the MAD2B cKO mice had more mushroom-like and long-like spines than the WT mice. Transmission electron microscopy (TEM) revealed that spine synapses increased and shaft synapses decreased in the CA1 of the MAD2B cKO mice. Taken together, our findings indicated that MAD2B plays an essential role in regulating learning and memory.

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Rab2 regulates presynaptic precursor vesicle biogenesis at the trans-Golgi

Cited by 20 publications

References 74 publications

End Binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles

End Binding protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles

Hesperetin Ameliorates Inhibition of Neuronal and Oligodendroglial Cell Differentiation Phenotypes Induced by Knockdown of Rab2b, an Autism Spectrum Disorder-Associated Gene Product

Conditional deletion of MAD2B in forebrain neurons enhances hippocampus-dependent learning and memory in mice

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