Neuron Navigator Research Articles

O-OGC06 Genomic analysis of response to neoadjuvant chemotherapy in oesophageal adenocarcinoma

Abstract Background Oesophageal adenocarcinoma (OAC) is the ninth most common cancer worldwide, with an estimated mortality of over 500,000 deaths yearly. Neoadjuvant chemotherapy (NAC) followed by surgery is the standard of care (SOC) for locally advanced OAC. Although almost all patients receive chemotherapy as SOC, fewer than 20% obtain a clinically meaningful response and benefit before surgery. The OAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. Methods To identify associations between genomic events and response to NAC in OAC, a comparative genomic analysis was performed in 65 patients using whole-genome sequencing. We defined response to NAC using Mandard Tumour Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n = 38). Results We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P = 0.036) and elevated copy number variation (CNV) in non-responders (282 vs 136/patient, P<0.001). We identified CNVs unique to each group, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of particular interest was the identification of the Neuron Navigator-3 (NAV3), a known tumour suppressor downstream of EGFR, which was mutated exclusively in non-responders with a frequency of 22%. Conclusions Our work characterises genetic features and mutations that are uniquely associated with response to NAC. We envision a treatment pipeline that incorporates driver mutation profiling in OAC, combining response prediction with targeted therapies to enhance response to NAC and improve survival outcomes.

Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes.

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).

Netrin‐1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson’s disease features

The netrin‐1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin‐1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin‐1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin‐1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin‐1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson’s disease (PD), we studied the potential impact of netrin‐1 in different animal models of PD. We demonstrate that both overexpression of netrin‐1 and brain administration of recombinant netrin‐1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin‐1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin‐1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin‐1 signaling in PD.

Macrophage-derived netrin-1 is critical for neuroangiogenesis in endometriosis

Netrin-1 is an extracellular guidance cue of neuronal navigation, mediated through interaction with its main receptors, and is known to be crucial in the development of multiple chronic inflammatory diseases. However, the expression pattern and mechanism of netrin-1 in endometriosis are currently undefined. Here we report that netrin-1 expression peaked in peritoneal macrophages found in endometriosis. Netrin-1 induced angiogenesis in ovarian endometriomas through interaction with CD146 in vascular endothelial cells. Through another receptor, neogenin, netrin-1 promoted neurite growth and sensitization in endometriosis through the up-regulation of MAP4, TAU, and CGRP. Targeted knockdown of neogenin in dorsal root ganglion (DRG) nerve cells compromised its response to netrin-1 through inhibiting phosphorylation of ERK1/2. The inhibition of netrin-1 using a neutralizing antibody reduced vascular and nerve infiltration in rat endometriotic lesions. In summary, our results suggest that netrin-1 is an important factor that promotes neuroangiogenesis in endometriosis.

Expression pattern of Nav2 in the murine CNS with development

Neuron navigator 2 (NAV2, RAINB1, POMFIL2, HELAD1, unc53H2) is essential for nervous system development. In the present study the spatial distribution of Nav2 transcript in mouse CNS during embryonic, postnatal and adult life is examined. Because multiple NAV2 proteins are predicted based on alternate promoter usage and RNA splicing, in situ hybridization was performed using probes designed to the 5′ and 3′ ends of the Nav2 transcript, and PCR products using primer sets spanning the length of the mRNA were also examined by real time PCR (qPCR). These studies support full-length Nav2 transcript as the predominant form in the wild-type mouse CNS. The developing cortex, hippocampus, thalamus, olfactory bulb, and granule cells (GC) within the cerebellum show the highest expression, with a similar staining pattern using either the 5′Nav2 or 3′Nav2 probe. Nav2 is expressed in GC precursors migrating over the cerebellar primordium as well as in the postmitotic premigratory cells of the external granule cell layer (EGL). It is expressed in the cornu ammonis (CA) and dentate gyrus (DG) throughout hippocampal development. In situ hybridization was combined with immunohistochemistry for Ki67, CTIP2 and Nissl staining to follow Nav2 transcript location during cortical development, where it is observed in neuroepithelial cells exiting the germinal compartments, as well as later in the cortical plate (CP) and developing cortical layers. The highest levels of Nav2 in all brain regions studied are observed in late gestation and early postnatal life which coincides with times when neurons are migrating and differentiating. A hypomorphic mouse that lacks the full-length transcript but expresses shorter transcript shows little staining in the CNS with either probe set except at the base of the cerebellum, where a shorter Nav2 transcript is detected. Using dual fluorescent probe in situ hybridization studies, these cells are identified as oligodendrocytes and are detected using both Olig1 and the 3′Nav2 probe. The identification of full-length Nav2 as the primary transcript in numerous brain regions suggests NAV2 could play a role in CNS development beyond that of its well-established role in the cerebellum.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

A 21‑gene Support Vector Machine classifier and a 10‑gene risk score system constructed for patients with gastric cancer.

Gastric cancer (GC) ranks fifth in terms of incidence and third in terms of tumor mortality worldwide. The present study was designed to construct a Support Vector Machine (SVM) classifier and risk score system for GC. The GSE62254 (training set) and GSE26253 (validation set 2) datasets were downloaded from the Gene Expression Omnibus database. Furthermore, the gene expression profile of GC (validation set 1) was obtained from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) between recurrent and non-recurrent samples were determined using the limma package. The feature genes were selected using the Caret package, and an SVM classifier was built using the e1071 package. Using the penalized package, the optimal predictive genes for constructing a risk score system were screened. Finally, stratification analysis of clinical factors and pathway enrichment analysis were performed using Gene Set Enrichment Analysis. A total of 239 DEGs were identified in GSE62254, among which 114 DEGs were significantly associated with both recurrence-free survival and overall survival. Subsequently, 21 feature genes were screened from the 114 DEGs, and an SVM classifier was built. A risk score system for survival prediction was constructed, following the selection of 10 optimal genes, including A-kinase anchoring protein 12, angiopoietin-like protein 1, cysteine-rich sequence 1, myeloid/lymphoid or mixed-lineage leukemia, translocated to chromosome 11, neuron navigator 3, neurobeachin, nephroblastoma overexpressed, pleiotrophin, tumor suppressor candidate 3 and zinc finger and SCAN domain containing 18. The stratification analysis revealed that pathological stage was an independent prognostic clinical factor in the high-risk group. Additionally, eight significant pathways were associated with the 10-gene signature. The SVM classifier and risk score system may be applied for classifying and predicting the prognosis of patients with GC, respectively.

Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

MicroRNA-18 promotes apoptosis of islet β-cells via targeting NAV1.

The detailed pathogenesis of diabetes mellitus (DM) remains to be fully elucidated. The purpose of the present study was to explore the role of microRNA (miR)-18 in DM and its underlying mechanisms, providing novel ideas for the treatment of the disease. After inflammatory factor-mediated induction, miR-18 expression in the islet β-cell line MIN6 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-18 mimics and miR-18 inhibitor were then constructed and transfected into MIN6 cells. The mRNA levels of pro-insulin in MIN6 cells were also detected by RT-qPCR. Released insulin levels and insulin secretion function of MIN6 cells were accessed by ELISA and glucose-stimulated insulin secretion assay, respectively. Apoptosis of MIN6 cells was detected by a terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end labeling assay and western blot analysis of apoptotic proteins. The binding interaction of miR-18 and neuron navigator 1(NAV1), a constituent of the phosphoinositide 3-kinase (PI3K)/AKT pathway, was assessed using a dual-luciferase reporter gene assay. Finally, the regulatory effect of miR-18 on the PI3K/AKT pathway was determined by western blot analysis. After induction of inflammatory factors in MIN6 cells, miR-18 expression was markedly upregulated. Transfection with miR-18 mimics inhibited pro-insulin levels, as well as insulin production and secretion capacity. miR-18 knockdown partially abrogated the inhibited insulin secretion capacity induced by interleukin-1β (IL-1β) treatment. In addition, apoptosis of MIN6 cells was increased by miR-18 mimics. The dual-luciferase reporter gene assay confirmed the direct binding of miR-18 to NAV1. Western blot analysis suggested that miR-18 markedly inhibited the PI3K/AKT pathway in MIN6 cells. In conclusion, miR-18 expression is upregulated by IL-1β induction in islet β-cells. It was demonstrated that miR-18 promotes apoptosis of islet β-cells at least partially by inhibiting NAV1 expression and insulin production via suppression of the PI3K/AKT pathway.

NAV2 facilitates invasion of cutaneous melanoma cells by targeting SNAI2 through the GSK-3β/β-catenin pathway.

Previous studies have identified neuron navigator 2(NAV2) as an oncogene in several human tumors. However, the NAV2 gene expression changes and its role in the pathogenesis of cutaneous melanoma have not been clearly illustrated. Further investigations of NAV2 in cutaneous melanoma may provide new mechanistic insight and treatment strategy for this disease. Through immunohistochemistry assay and bioinformatics analysis, we found that melanoma tissues showed an upregulated expression of NAV2 which correlated with poor prognosis of cutaneous melanoma. To investigate the effect of NAV2 on the proliferation and invasion of melanoma, shNAV2 and NAV2-cDNA were transfected into melanoma cell lines. NAV2 overexpression significantly promoted melanoma cell proliferation, migration and invasion, while NAV2 silencing effectively inhibited this process. The potential underlying mechanisms were investigated using bioinformatics analysis, qRT-PCR, and western blot. Results showed that NAV2-mediated invasion of melanoma cells was driven by enhanced epithelial-mesenchymal transition, which was resulted from SNAI2 upregulation via the GSK-3β/β-catenin pathway. This study suggested that NAV2 could induce melanoma proliferation and invasion by epithelial-mesenchymal transition through the GSK-3β/β-catenin-SNAI2 pathway. Our findings on the pathological mechanisms of NAV2-associated cutaneous melanoma may contribute to the development of potential therapeutic strategy for melanoma.

Nature vs. nurture in human sociality: multi-level genomic analyses of social conformity.

Social conformity is fundamental to human societies and has been studied for more than six decades, but our understanding of its mechanisms remains limited. Individual differences in conformity have been attributed to social and cultural environmental influences, but not togenes. Here we demonstrate agenetic contribution to conformity after analyzing 1,140 twins and single-nucleotide polymorphism (SNP)-based studies of 2,130 young adults. A two-step genome-wide association study (GWAS) revealed replicable associations in 9 genomic loci, and a meta-analysis of three GWAS with a sample size of ~2,600 further confirmed one locus, corresponding to the NAV3 (Neuron Navigator 3) gene which encodes a protein important for axon outgrowth and guidance. Further multi-level (haplotype, gene, pathway) GWAS strongly associated genes including NAV3, PTPRD(protein tyrosine phosphatase receptor type D), ARL10 (ADP ribosylation factor-like GTPase 10), and CTNND2 (catenin delta 2), with conformity. Magnetic resonance imaging of 64 subjects shows correlation of activation or structural features of brain regions with the SNPs of these genes, supporting their functional significance. Our results suggest potential moderate genetic influence on conformity, implicate several specific genetic elements in conformity and will facilitate further research on cellular and molecular mechanisms underlying human conformity.

Long noncoding RNA expression profile reveals lncRNAs signature associated with extracellular matrix degradation in kashin-beck disease

Kashin-Beck disease (KBD) is a deformative, endemic osteochondropathy involving degeneration and necrosis of growth plates and articular cartilage. The pathogenesis of KBD is related to gene expression and regulation mechanisms, but long noncoding RNAs (lncRNAs) in KBD have not been investigated. In this study, we identified 316 up-regulated and 631 down-regulated lncRNAs (≥ 2-fold change) in KBD chondrocytes using microarray analysis, of which more than three-quarters were intergenic lncRNAs and antisense lncRNAs. We also identified 232 up-regulated and 427 down-regulated mRNAs (≥ 2-fold change). A lncRNA-mRNA correlation analysis combined 343 lncRNAs and 292 mRNAs to form 509 coding-noncoding gene co-expression networks (CNC networks). Eleven lncRNAs were predicted to have cis-regulated target genes, including NAV2 (neuron navigator 2), TOX (thymocyte selection-associated high mobility group box), LAMA4 (laminin, alpha 4), and DEPTOR (DEP domain containing mTOR-interacting protein). The differentially expressed mRNAs in KBD significantly contribute to biological events associated with the extracellular matrix. Meanwhile, 34 mRNAs and 55 co-expressed lncRNAs constituted a network that influences the extracellular matrix. In the network, FBLN1 and LAMA 4 were the core genes with the highest significance. These novel findings indicate that lncRNAs may play a role in extracellular matrix destruction in KBD.

Family-based association analysis of NAV2 gene with the risk and age at onset of Alzheimer's disease

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p=8.46×10−4) and 11 SNPs were associated with AAO (top SNP rs1354269 with p=2.87×10−3). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk (p=1.7×10−2 and 2.71×10−2; respectively) and AAO (p=1.85×10−3 and 6.06×10−3; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.

Neuron navigator-2 and cyclin D2 are new candidate prognostic markers in uterine sarcoma.

The objective of this study was to validate the diagnostic and clinical role of four protein products of genes previously found to be differentially expressed in uterine low-grade endometrial stromal sarcoma (LG-ESS) compared to uterine leiomyosarcoma (LMS). Protein expression by immunohistochemistry of transgelin (TGLN), neuron navigator-2 (NAV2), fatty acid binding protein-3 (FABP3), and cyclin D2 (CCND2) was analyzed in 305 uterine sarcomas (231 LMS, 74 LG-ESS). Expression was analyzed for association with clinicopathologic parameters and survival. TGLN (p<0.001), NAV2 (p<0.001), and FABP3 (p=0.005) were overexpressed in LMS compared to LG-ESS, whereas nuclear CCND2 (p<0.001) was overexpressed in LG-ESS. NAV2 expression was associated with shorter overall survival in patients with LMS (p=0.037), whereas nuclear CCND2 expression in LG-ESS was significantly related to longer survival (p=0.012) in univariate analysis. Nuclear CCND2 expression was an independent prognosticator in Cox multivariate analysis (p=0.023). In conclusion, TGLN, FABP3, NAV2, and nuclear CCND2 aid in differentiating LG-ESS from LMS. NAV2 and CCND2 are novel candidate prognostic markers in LMS and LG-ESS, respectively.

Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction

BackgroundAlthough renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy.ResultsWe have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model. Several hundreds of miRNAs and mRNAs displayed changed abundance during disease. Combination of miRNAs in both species and associated mRNAs let to the prioritization of five miRNAs and 35 mRNAs associated to disease. In vitro and in vivo validation identified consistent dysregulation of let-7a-5p and miR-29-3p and new potential targets, E3 ubiquitin-protein ligase (DTX4) and neuron navigator 1 (NAV1), potentially involved in fibrotic processes, in obstructive nephropathy in both human and mice that would not be identified otherwise.ConclusionsOur study is the first to correlate a mouse model of neonatal partial UUO with human UPJ obstruction in a comprehensive systems biology analysis. Our data revealed let-7a and miR-29b as molecules potentially involved in the development of fibrosis in UPJ obstruction via the control of DTX4 in both man and mice that would not be identified otherwise.

Transcriptomic profiling of platelet senescence and platelet extracellular vesicles.

Platelets (PLTs) are derived from megakaryocytes during PLT shedding. Senescent or activated PLTs are expanded in vascular and neurological diseases and release PLT extracellular vesicles (PL-EVs). A systematic analysis of regular messenger RNA (mRNA) and small RNA composition in PLTs and PL-EVs during in vitro PLT senescence has not yet been published. We isolated PLTs, total PL-EVs, and PL-EV subsets on Days 0 and 5 from human stored donor platelet concentrates. Isolated mRNA species and microRNA (miRNA) species were analyzed by microarrays and deep sequencing. Correlation of mRNA and miRNA species (miR) and miRNA target analyses were performed using bioinformatics. During in vitro PLT senescence, residual PLT mRNA species were decreased and partially converted to miRNA species. Residual mRNAs included encoded genes relevant for atherosclerosis, inflammation (matrix metallopeptidase 14 [MMP-14], granulin [GRN], angiopoietin like 2 [ANGPTL2]), and neurotransmission (dopamine receptor 2 [DRD2], γ-aminobutyric acid type A receptor ρ3 [GABRR3]). Compared with senescent PLTs, PL-EVs have up-regulated their miRNA species involved in "diabesity" and in vascular and metabolic disease (miR-144-3p, miR-486-5p, miR-142-5p, miR-451a, miR-25-3p, miR-145-5p, and let-7f-5p). The 100 highest expressed PL-EV miRNA species determined by microarrays were compared with the 100 highest expressed PL-EV miRNA species detected by deep sequencing. This approach resulted in 66 overlaps. The regulated miRNAs (assessed by both methods) were related to neurological disorders, including targets for Alzheimer's disease (e.g., β-site amyloid precursor protein APP-cleaving enzyme 1 [BACE1], translocase of outer mitochondrial membrane 40 homolog [TOMM40], neuron navigator 3 [NAV3]). During in vitro senescence, PLTs degrade large RNA species. Concomitantly, they up-regulate a distinct set of known small RNA species involved in atherosclerosis, inflammation, and neurodegeneration. PL-EVs enrich miRNA species, likely supporting the role of PLTs and PL-EVs in vascular homeostasis and as carriers of neurodegenerative disease-related miRNA cargo.

Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression.

The antiphospholipid syndrome (APS) is characterised by venous and/or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, β2glycoprotein 1 (anti-β2GPI), and IgG against domain 1 of β2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-β2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-β2GPI antibodies. Expression analysis confirmed increased expression of TNFα in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS.

Neuron navigator 2 overexpression indicates poor prognosis of colorectal cancer and promotes invasion through the SSH1L/cofilin-1 pathway.

BackgroundNeuron navigator 2 (NAV2) encodes a member of the neuron navigator gene family, which plays a role in tumorigenesis and cell migration. However, the prognostic value of NAV2 expression in colorectal cancer (CRC) patients and the potential pathway through which NAV2 promotes migration and invasion in CRC cell lines is poorly understood.MethodsThe expression level of NAV2 was detected in CRC tissues from two different CRC cohorts by immunohistochemistry, qRT-PCR and Western blotting; the correlation between NAV2 expression and clinicopathological characters was analyzed, and the prognostic value of NAV2 expression was analyzed using a Cox regression model. CRC cell lines with NAV2 knocked out were used to validate the function and potential pathway used by NAV2 to promote CRC cell migration and invasion.ResultsThe results showed that NAV2 was overexpressed in CRC tissues, and it was closely correlated with depth of invasion, and lymph and distant metastasis. Multivariate analysis indicated that high NAV2 expression was a poor prognostic indicator of recurrence-free survival and overall survival in CRC patients. Furthermore, Cox regression analysis revealed that high NAV2 expression integrated with high tumor budding grade was a powerful independent predictive factor of CRC clinical outcome. In vitro and in vivo assays demonstrated that knockdown of NAV2 led to reduced migration and invasion of cancer cells, and the process involved the regulation of F-actin polymerization through the SSH1L/cofilin-1 pathway.ConclusionBased on these findings, NAV2 could serve as both a prognostic biomarker and a potential therapeutic target for patients with NAV2-positive CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0237-3) contains supplementary material, which is available to authorized users.

The nav2 (neuron navigator 2) gene as a common genetic influence across correlated episodic memory performances

The nav2 (neuron navigator 2) gene as a common genetic influence across correlated episodic memory performances

The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway.

The Rac-Cofilin pathway is essential for cytoskeletal remodeling to control axonal development. Rac signals through the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth and through a Pak-independent non-canonical pathway to promote outgrowth. Whether this non-canonical pathway converges to promote Cofilin-dependent F-actin reorganization in axonal growth remains elusive. We demonstrate that Sickie, a homolog of the human microtubule-associated protein neuron navigator 2, cell-autonomously regulates axonal growth of Drosophila mushroom body (MB) neurons via the non-canonical pathway. Sickie was prominently expressed in the newborn F-actin-rich axons of MB neurons. A sickie mutant exhibited axonal growth defects, and its phenotypes were rescued by exogenous expression of Sickie. We observed phenotypic similarities and genetic interactions among sickie and Rac-Cofilin signaling components. Using the MARCM technique, distinct F-actin and phospho-Cofilin patterns were detected in developing axons mutant for sickie and Rac-Cofilin signaling regulators. The upregulation of Cofilin function alleviated the axonal defect of the sickie mutant. Epistasis analyses revealed that Sickie suppresses the LIMK overexpression phenotype and is required for Pak-independent Rac1 and Slingshot phosphatase to counteract LIMK. We propose that Sickie regulates F-actin-mediated axonal growth via the non-canonical Rac-Cofilin pathway in a Slingshot-dependent manner.