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Background: Neurons are highly specialized cells with a complex morphology generated by various membrane trafficking steps. They contain Golgi outposts in dendrites, which are formed from somatic Golgi tubules. In trafficking membrane fusion is mediated by a specific combination of SNARE proteins. A functional SNARE complex contains four different helices, one from each SNARE subfamily (R-, Qa, Qb and Qc). Loss of the two Qb SNAREs vti1a and vti1b from the Golgi apparatus and endosomes leads to death at birth in mice with massive neurodegeneration in peripheral ganglia and defective axon tracts. Methods: Hippocampal and cortical neurons were isolated from Vti1a−/−Vti1b−/− double deficient, Vti1a−/−Vti1b+/−, Vti1a+/−Vti1b−/− and Vti1a+/−Vti1b+/− double heterozygous embryos. Neurite outgrowth was determined in cortical neurons and after stimulation with several neurotrophic factors or the Rho-associated protein kinase ROCK inhibitor Y27632, which induces exocytosis of enlargeosomes, in hippocampal neurons. Moreover, postsynaptic densities were isolated from embryonic Vti1a−/−Vti1b−/− and Vti1a+/−Vti1b+/− control forebrains and analyzed by western blotting. Results: Golgi outposts were present in Vti1a−/−Vti1b+/− and Vti1a+/−Vti1b−/− dendrites of hippocampal neurons but not detected in the absence of vti1a and vti1b. The length of neurites was significantly shorter in double deficient cortical neurons. These defects were not observed in Vti1a−/−Vti1b+/− and Vti1a+/−Vti1b−/− neurons. NGF, BDNF, NT-3, GDNF or Y27632 as stimulator of enlargeosome secretion did not increase the neurite length in double deficient hippocampal neurons. Vti1a−/−Vti1b−/− postsynaptic densities contained similar amounts of scaffold proteins, AMPA receptors and NMDA receptors compared to Vti1a+/−Vti1b+/−, but much more TrkB, which is the receptor for BDNF. Conclusion: The absence of Golgi outposts did not affect the amount of AMPA and NMDA receptors in postsynaptic densities. Even though TrkB was enriched, BDNF was not able to stimulate neurite elongation in Vti1a−/−Vti1b−/− neurons. Vti1a or vti1b function as the missing Qb-SNARE together with VAMP-4 (R-SNARE), syntaxin 16 (Qa-SNARE) and syntaxin 6 (Qc-SNARE) in induced neurite outgrowth. Our data show the importance of vti1a or vti1b for two pathways of neurite elongation. [ABSTRACT FROM AUTHOR]

Vesicle transport through interaction with t-SNAREs 1A (Vti1a), a member of the N-ethylmaleimide-sensitive factor attachment protein receptor protein family, is involved in cell signaling as a vesicular protein and mediates vesicle trafficking. Vti1a appears to have specific roles in neurons, primarily by regulating upstream neurosecretory events that mediate exocytotic proteins and the availability of secretory organelles, as well as regulating spontaneous synaptic transmission and postsynaptic efficacy to control neurosecretion. Vti1a also has essential roles in neural development, autophagy, and unconventional extracellular transport of neurons. Studies have shown that Vti1a dysfunction plays critical roles in pathological mechanisms of Hepatic encephalopathy by influencing spontaneous neurotransmission. It also may have an unknown role in amyotrophic lateral sclerosis. A VTI1A variant is associated with the risk of glioma, and the fusion product of the VTI1A gene and the adjacent TCF7L2 gene is involved in glioma development. This review summarizes Vti1a functions in neurons and highlights the role of Vti1a in the several nervous system disorders. [ABSTRACT FROM AUTHOR]

Recent work has revealed that spontaneous release plays critical roles in the central nervous system, but how it is regulated remains elusive. Here, we report that synaptotagmin‐11 (Syt11), a Ca2+‐independent Syt isoform associated with schizophrenia and Parkinson's disease, suppressed spontaneous release. Syt11‐knockout hippocampal neurons showed an increased frequency of miniature excitatory post‐synaptic currents while over‐expression of Syt11 inversely decreased the frequency. Neither knockout nor over‐expression of Syt11 affected the average amplitude, suggesting the pre‐synaptic regulation of spontaneous neurotransmission by Syt11. Glutathione S‐transferase pull‐down, co‐immunoprecipitation, and affinity‐purification experiments demonstrated a direct interaction of Syt11 with vps10p‐tail‐interactor‐1a (vti1a), a non‐canonical SNARE protein that maintains spontaneous release. Importantly, knockdown of vti1a reversed the phenotype of Syt11 knockout, identifying vti1a as the main target of Syt11 inhibition. Domain analysis revealed that the C2A domain of Syt11 bound vti1a with high affinity. Consistently, expression of the C2A domain alone rescued the phenotype of elevated spontaneous release in Syt11‐knockout neurons similar to the full‐length protein. Altogether, our results suggest that Syt11 inhibits vti1a‐containing vesicles during spontaneous release. [ABSTRACT FROM AUTHOR]

The quantal content of an evoked postsynaptic response is typically determined by dividing it by the average spontaneous miniature response. However, this approach is challenged by the notion that different synaptic vesicle pools might drive spontaneous and evoked release. Here, we "silence" synaptic vesicles through pharmacological alkalinization and subsequently rescue them by optogenetic acidification. We find that such silenced synaptic vesicles, retrieved during evoked or spontaneous activity, cross-deplete the complementary release mode in a fully reversible manner. A fluorescently tagged version of the endosomal SNARE protein Vti1a, which has been suggested to identify a separate pool of spontaneously recycling synaptic vesicles, is trafficked to synaptic vesicles significantly only upon overexpression but not when endogenously tagged by CRISPR-Cas9. Thus, both release modes draw synaptic vesicles from the same readily releasable pool. [Display omitted] • The optogenetic proton pump pHoenix enables reversible "silencing" of synaptic vesicles • Silencing synaptic vesicles fusing spontaneously reduces the evoked release amplitude • Silencing synaptic vesicles fusing during activity reduces the mini frequency • An endogenously tagged endosomal SNARE Vti1a marginally localizes to presynapses Duan et al. utilize the optogenetic proton pump pHoenix to reversibly silence synaptic vesicles. They find that silenced synaptic vesicles, retrieved during evoked or spontaneous activity, cross-deplete the complementary release mode in a fully reversible manner. Thus, these synaptic vesicles are drawn from a common pool. [ABSTRACT FROM AUTHOR]

The Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family mediates membrane fusion during membrane trafficking and autophagy in all eukaryotic cells, with a number of SNAREs having cell type-specific functions. The endosome-trans-Golgi network (TGN) localized SNARE, Vesicle transport through interaction with t-SNAREs 1A (Vti1a), is unique among SNAREs in that it has numerous neuron-specific functions. These include neurite outgrowth, nervous system development, spontaneous neurotransmission, synaptic vesicle and dense core vesicle secretion, as well as a process of unconventional surface transport of the Kv4 potassium channel. Furthermore, the human VT11A gene is known to form fusion products with neighboring genes in cancer tissues, and VT11A variants are associated with risk in cancers, including glioma. In this review, I highlight VTI1A's known physio-pathological roles in brain neurons, as well as unanswered questions in these regards.

Genetic studies have linked the VTI1A- TCF7L2 region with risk of multiple cancers. However, findings from these studies were generally inconclusive. We aimed to provide a synopsis of current understanding of associations between variants in the VTI1A- TCF7L2 region and cancer susceptibility. We conducted a comprehensive research synopsis and meta-analysis to evaluate associations between 17 variants in this region and risk of seven cancers using data from 32 eligible articles totaling 224,656 cancer cases and 324,845 controls. We graded cumulative evidence of significant associations using Venice criteria and false-positive report probability tests. We also conducted analyses to evaluate potential function of these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project. Eight variants showed a nominally significant association with risk of individual cancer ( p < 0.05). Cumulative epidemiological evidence of an association was graded as strong for rs7903146 [odds ratio (OR) = 1.05, p = 4.13 × 10−5] and rs7904519 (OR = 1.07, p = 2.02 × 10−14) in breast cancer, rs11196172 (OR = 1.11, p = 2.22 × 10−16), rs12241008 (OR = 1.13, p = 1.36 × 10−10) and rs10506868 (OR = 1.10, p = 3.98 × 10−9) in colorectal cancer, rs7086803 in lung cancer (OR = 1.30, p = 3.54 × 10−18) and rs11196067 (OR = 1.18, p = 3.59 × 10−13) in glioma, moderate for rs12255372 (OR = 1.12, p = 2.52 × 10−4) in breast cancer and weak for rs7903146 (OR = 1.11, p = 0.007) in colorectal cancer. Data from ENCODE suggested that seven variants with strong evidence and other correlated variants might fall within putative functional regions. Collectively, our study provides summary evidence that common variants in the VTI1A and TCF7L2 genes are associated with risk of breast, colorectal, lung cancer and glioma and highlights the significant role of the VTI1A- TCF7L2 region in the pathogenesis of human cancers. [ABSTRACT FROM AUTHOR]

Background VTI1A and ETFA were identified recently as susceptibility genes for non-glioblastoma (GBM) of glioma risk in European populations, but the genetic etiology and pathogenesis of glioma have not been fully elucidated. Here, we aimed to investigate whether common genetic variants in VTI1A and ETFA predispose Han Chinese individuals to glioma. Methods The association of thirteen common tagging single nucleotide polymorphisms (SNPs) in VTI1A and ETFA genes with glioma were assessed in a hospital-based case-control study including 473 non-GBM of glioma patients and 1046 cancer-free controls. Results Two SNPs (rs11196067 in VTI1A and rs1801591 in ETFA ) were found to be significantly associated with non-GBM of glioma risk (rs11196067, adjusted P = 0.00018, adjusted odds ratio (OR) = 1.37, 95% confidence interval (CI) = 1.16–1.61; rs1801591, adjusted P = 0.000022, adjusted OR = 1.72, 95% CI = 1.34–2.20). In further stratified analysis, they were both more pronounced in the adult subgroup. In haplotype-based analysis, two haplotypes were identified to be significant association with glioma. The haplotype “TGA” ( P = 0.002) in VTI1A and the haplotype “ACA” ( P < 0.001) in ETFA had a 1.5-fold and 3-fold increased glioma risk respectively, compared with corresponding non-carriers. Conclusions In summary, our results indicate that genetic variants in VTI1A and ETFA may modify individual susceptibility to non-GBM of glioma in the Han Chinese population and support the role of the VTI1A and ETFA genes in the occurrence of glioma. [ABSTRACT FROM AUTHOR]

Abstract: Exocytosis involves membrane fusion between secretory vesicles and the plasma membrane. The Soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAPs) and their receptor proteins (SNAREs) interact to fuse vesicles with the membrane and trigger the release of their sialosecretome out of the tick salivary gland cells. In this study, we examined the functional significance of the Vti family of SNARE proteins of blood-feeding Amblyomma maculatum and Amblyomma americanum. Vti1A and Vti1B have been implicated in multiple functional roles in vesicle transport. QRT-PCR studies demonstrated that the highest transcriptional expression of vti1a and vti1b genes occurs in unfed salivary glands, suggesting that elevated secretory vesicle formation occurs prior to feeding but continues at low rates after blood feeding commences. Vti1A and Vti1B localize to the secretory vesicles in unfed tick salivary glands in immunofluorescence microscopy studies. Knockdown of vti1a and vti1b by RNA interference resulted in a significant decrease in the engorged tick weight compared to the control during prolonged blood-feeding on the host. RNA interference of vti1a or vti1b impaired oviposition and none of the ticks produced eggs masses. Surprisingly, the double knockdown did not produce a strong phenotype and ticks fed normally on the host and produced egg masses, suggesting a compensatory mechanism exists within the secretory system which may have been activated in the double knockdown. These results suggest an important functional role of the Vti family of SNARE proteins in tick blood feeding and ultimately oviposition. Understanding the basic functions of the Vti family of SNARE proteins in salivary glands may lead to better ways to prevent tick attachment and transmission of tick-borne diseases. [Copyright &y& Elsevier]

An increasing number of studies suggest that distinct pools of synaptic vesicles drive specific forms of neurotransmission. Interspersed with these functional studies are analyses of the synaptic vesicle proteome which have consistently detected the presence of so-called "non-canonical" SNAREs that typically function in fusion and trafficking of other subcellular structures within the neuron. The recent identification of certain non-canonical vesicular SNAREs driving spontaneous (e.g., VAMP7 and vti1a) or evoked asynchronous (e.g., VAMP4) release integrates and corroborates existing data from functional and proteomic studies and implies that at least some complement of non-canonical SNAREs resident on synaptic vesicles function in neurotransmission. Here, we discuss the specific roles in neurotransmission of proteins homologous to each member of the classical neuronal SNARE complex consisting of synaptobrevin2, syntaxin-1, and SNAP-25. [ABSTRACT FROM AUTHOR]