The Exocyst Component Exo70 Modulates Dendrite Arbor Formation, Synapse Density, and Spine Maturation in Primary Hippocampal Neurons

Lira, Matías; Arancibia, Duxan; Orrego, Patrício R.; Montenegro-Venegas, Carolina; Cruz, Yocelin; García, Jonathan; Leal-Ortiz, Sergio; Godoy, Juan A.; Gundelfinger, Eckart D.; Inestrosa, Nibaldo C.; Garner, Craig C.; Zamorano, Pedro; Torres, Viviana

doi:10.1007/s12035-018-1378-0

Cited by 22 publications

(42 citation statements)

References 81 publications

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“…In yeast, exocytosis of these PM-expanding vesicles requires tethering to PM by exocyst, without which soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes required for the membrane fusion do not form (TerBush et al, 1996;Grote et al, 2000). In neurons, their contribution to the growth of neurites (Vega and Hsu, 2001;Murthy et al, 2003)-and more specifically dendrites (Peng et al, 2015;Zou et al, 2015;Lira et al, 2019)-has been observed in Drosophila and cultured mammalian neurons. Interestingly, exocyst seems to be dispensable for neurotransmitter secretion in Drosophila (Murthy et al, 2003;Mehta et al, 2005), but not in primary hippocampal neurons (Lira et al, 2019).…”

Section: Basic Mechanisms Of Pm Turnover In Neurons: Endocytosis and mentioning

confidence: 99%

“…In neurons, their contribution to the growth of neurites (Vega and Hsu, 2001;Murthy et al, 2003)-and more specifically dendrites (Peng et al, 2015;Zou et al, 2015;Lira et al, 2019)-has been observed in Drosophila and cultured mammalian neurons. Interestingly, exocyst seems to be dispensable for neurotransmitter secretion in Drosophila (Murthy et al, 2003;Mehta et al, 2005), but not in primary hippocampal neurons (Lira et al, 2019). Generally, for membranes to fuse, SNARE proteins must be present on both membranous systems (Südhof and Rothman, 2009).…”

Section: Basic Mechanisms Of Pm Turnover In Neurons: Endocytosis and mentioning

confidence: 99%

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Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Chung

Park

et al. 2020

Front. Cell. Neurosci.

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Due to their enormous surface area compared to other cell types, neurons face unique challenges in properly handling supply and retrieval of the plasma membrane (PM)-a process termed PM turnover-in their distal areas. Because of the length and extensiveness of dendritic branches in neurons, the transport of materials needed for PM turnover from soma to distal dendrites will be inefficient and quite burdensome for somatic organelles. To meet local demands, PM turnover in dendrites most likely requires local cellular machinery, such as dendritic endocytic and secretory systems, dysregulation of which may result in dendritic pathology observed in various neurodegenerative diseases (NDs). Supporting this notion, a growing body of literature provides evidence to suggest the pathogenic contribution of dysregulated PM turnover to dendritic pathology in certain NDs. In this article, we present our perspective view that impaired dendritic endocytic and secretory systems may contribute to dendritic pathology by encumbering PM turnover in NDs.

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Section: Basic Mechanisms Of Pm Turnover In Neurons: Endocytosis and mentioning

confidence: 99%

Section: Basic Mechanisms Of Pm Turnover In Neurons: Endocytosis and mentioning

confidence: 99%

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Chung

Park

et al. 2020

Front. Cell. Neurosci.

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“…Neurotransmitter release from synaptic vesicles is, at least in Drosophila, independent of exocyst, but the complex is required for all other known types of vesicles, including the insertion of AMPA receptors into the postsynaptic membrane (Murthy et al, 2003). Exocyst is also needed for dendrite arbor formation and spine maturation in hippocampal neurons (Lira et al, 2019;Vega and Hsu, 2001). Components of the exocyst complex are enriched in actin-containing growth cones, synaptic boutons, and filopodia (Hazuka et al, 1999;Koon et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the exocyst component EXOC2 cause severe defects in human brain development

Bergen

Ahmed

Collins

et al. 2020

Journal of Experimental Medicine

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The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected individuals have severe developmental delay, dysmorphism, and brain abnormalities; variability associated with epilepsy; and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.

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“…Significantly, these Sec3 and Exo84 are components of different subcomplexes and likely interact with phospholipids through their PH domains. The exocyst has clear roles in secretion but is also implicated in disease susceptibility, host cell invasion by intracellular bacteria and development ( Arasaki et al , 2018; Bonnemaijer et al , 2018; Lira et al , 2018) with evidence for additional roles in endocytosis/recycling also published ( Boehm et al , 2017; Jose et al , 2015; Monteiro et al , 2013). Also the tetrameric subcomplexes function in autophagy with potential for additional specialisation ( Bodemann et al , 2011; Kulich et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

“…For example, in the abstract the authors write, “The exocyst complex is involved in late exocytosis, and possibly additional pathways, and is a member…”. In the introduction, the authors describe some of the other additional pathways, “The exocyst has clear roles in secretion but is also implicated in disease susceptibility, host cell invasion by intracellular bacteria and development (Arasaki et al, 2018 1 ; Bonnemaijer et al, 2018 2 ; Lira et al, 2019 3 ) with evidence for additional roles in endocytosis/recycling also published (Boehm et al, 2017 4 ; Jose et al, 2015 5 )”. This is not a complete list as the exocyst has also been shown to be centrally involved in basolateral protein transport (Grindstaff et al, Cell, 1998 6 ), ciliogenesis (Zuo et al, Mol Biol Cell, 2009 7 ), and protein translocation in the ER (Toikkanen et al, J Biol Chem, 2003 8 ; Lipschutz et al, J Biol Chem, 2003 9 ).…”

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confidence: 99%

Evolution of late steps in exocytosis: conservation and specialization of the exocyst complex

Boehm¹,

Field²

2019

Wellcome Open Res

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Background: The eukaryotic endomembrane system most likely arose via paralogous expansions of genes encoding proteins that specify organelle identity, coat complexes and govern fusion specificity. While the majority of these gene families were established by the time of the last eukaryotic common ancestor (LECA), subsequent evolutionary events has moulded these systems, likely reflecting adaptations retained for increased fitness. As well as sequence evolution, these adaptations include loss of otherwise canonical components, the emergence of lineage-specific proteins and paralog expansion. The exocyst complex is involved in late exocytosis and additional trafficking pathways and a member of the complexes associated with tethering containing helical rods (CATCHR) tethering complex family. CATCHR includes the conserved oligomeric Golgi (COG) complex, homotypic fusion and vacuole protein sorting (HOPS)/class C core vacuole/endosome tethering (CORVET) complexes and several others. The exocyst is integrated into a complex GTPase signalling network in animals, fungi and other lineages. Prompted by discovery of Exo99, a non-canonical subunit in the excavate protist Trypanosoma brucei, and availability of significantly increased genome sequence data, we re-examined evolution of the exocyst. Methods: We examined the evolution of exocyst components by comparative genomics, phylogenetics and structure prediction. Results: The exocyst composition is highly conserved, but with substantial losses of subunits in the Apicomplexa and expansions in Streptophyta plants, Metazoa and land plants, where for the latter, massive paralog expansion of Exo70 represents an extreme and unique example. Significantly, few taxa retain a partial complex, suggesting that, in general, all subunits are probably required for functionality. Further, the ninth exocyst subunit, Exo99, is specific to the Euglenozoa with a distinct architecture compared to the other subunits and which possibly represents a coat system. Conclusions: These data reveal a remarkable degree of evolutionary flexibility within the exocyst complex, suggesting significant diversity in exocytosis mechanisms.

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The Exocyst Component Exo70 Modulates Dendrite Arbor Formation, Synapse Density, and Spine Maturation in Primary Hippocampal Neurons

Cited by 22 publications

References 81 publications

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Mutations in the exocyst component EXOC2 cause severe defects in human brain development

Evolution of late steps in exocytosis: conservation and specialization of the exocyst complex

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