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Schlegel, Martin, Monika Sharma, Emily J. Brown, Alexandra A. C. Newman, Yannick Cyr, Milessa Silva Afonso, Emma M. Corr, et al. "Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression." Circulation Research 129, no. 5 (August 20, 2021): 530–46. http://dx.doi.org/10.1161/circresaha.121.319313.
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Rationale: Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid-lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response and that targeting factors that hinder inflammation resolution will facilitate plaque regression. Objective: The guidance molecule Ntn1 (netrin-1) is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing Ntn1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques. Methods and Results: To temporally silence Ntn1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre recombinase ( Ntn1 fl/fl Cx3cr1 creERT2+ ) and littermate control mice ( Ntn1 fl/fl Cx3cr1 WT ). Mice were fed Western diet in the setting of hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression to render them atherosclerotic and then treated with tamoxifen to initiate deletion of myeloid Ntn1 (Mø ΔNtn1 ) or not in controls (Mø WT ). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (−50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in Mø ΔNtn1 compared with Mø WT plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon Ntn1 silencing. Single-cell RNA sequencing of aortic immune cells before and after Ntn1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from Mø ΔNtn1 mice showed hallmarks of inflammation resolution, including higher levels of proresolving macrophages, IL (interleukin)-10, and efferocytosis, as compared to plaques from Mø WT mice. Conclusion: Our data show that targeting Ntn1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.
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Dudgeon, Crissy, Anthony Casabianca, Chris Harris, Igor Astsaturov, Charline Ogier, Xiaoyang Su, Jason Pitarresi, et al. "Abstract B020: Retinoic acid produced by hepatic stellate cells facilitates Netrin-1 mediated pancreatic cancer metastasis." Cancer Research 82, no. 22_Supplement (November 15, 2022): B020. http://dx.doi.org/10.1158/1538-7445.panca22-b020.
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Abstract A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its proclivity for metastasis as evidenced by the fact that 85% are stage IV at diagnosis. This highlights the need to better understand the biology of metastatic PDAC and identify novel therapies for this patient population. Axon guidance genes have been shown to be involved in PDAC progression, but their role is unclear. We have investigated the role of the axon guidance molecule Netrin-1 and its receptors Unc5b and DCC in PDAC. We found that in both murine and human samples that NTN1 expression is increased in metastatic PDAC and the quasi-mesenchymal subtype. Murine and TCGA data indicate that Unc5b is the dominant NTN1 receptor and genetic knock-down (KD) or knock-out (KO) of either Netrin-1 or Unc5b decreases migration, invasion, and cell survival in vitro and hepatic metastatic growth in vivo. The mechanism of Netrin-1 upregulation in metastatic PDAC is unknown. We found that hepatic stellate cell (HSC) secreted retinoic acid upregulates NTN1 through both an RXR/RAR and Elf mediated mechanism. To determine if NTN1 is involved in the process of HSC activation we found that recombinant NTN1 added to HSCs in vitro induced activation. We examined the livers of mice harboring orthotopic PDAC tumors using murine pancreatic cancer lines that were either NTN1 wild type (WT) or KO, and found that the NTN-expressing lines increased HSC activation providing evidence that NTN1 is important for long distance intercellular communication between primary pancreatic tumors and the pre-metastatic liver. We detected NTN1 within extracellular vesicles, and mice pre-conditioned with EVs from NTN1 KO cells demonstrated a decreased metastatic burden as compared mice preconditioned with NTN1 WT cells. Treatment of several murine PDAC models (autochthonous and metastatic) with a monoclonal antibody to NTN1 led to decreased metastases and increased survival. These studies reveal that NTN1 is upregulated in metastatic PDAC mediated by a novel mechanism that involves EVs, HSC activation and RXR/RAR signaling. These studies provide pre-clinical evidence to support a human clinical trial of anti-NTN1 therapy in PDAC. Citation Format: Crissy Dudgeon, Anthony Casabianca, Chris Harris, Igor Astsaturov, Charline Ogier, Xiaoyang Su, Jason Pitarresi, Wade Narrow, Fady Soliman, Tracy Withers, Patrick Mehlen, Darren Carpizo. Retinoic acid produced by hepatic stellate cells facilitates Netrin-1 mediated pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B020.
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Ochiai, Yosuke, Sunagawa Masaki, Ermanno Malagola, Hiroki Kobayashi, Feijing Wu, Ruth A. White, Leah B. Zamechek, and Timothy C. Wang. "Abstract B100: Netrin-1/Neogenin-1 interaction modulates pancreatic innervation to promote tumorigenesis and accelerates cancer progression." Cancer Research 84, no. 2_Supplement (January 16, 2024): B100. http://dx.doi.org/10.1158/1538-7445.panca2023-b100.
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Abstract Background: Nerves are a major component of the tumor microenvironment, with active crosstalk between cancer cells and nerves that may contribute to cancer progression. Netrin1 (Ntn1) is an axon guidance molecule that is important during early neural development. Recent studies suggest that Ntn1 may also play a role in tumorigenesis but its role in pancreatic cancer is not well understood. We hypothesized that Ntn1 plays a pro-tumorigenic role in pancreatic ductal adenocarcinoma (PDAC) progression and metastasis in part through modulation of nerves in the microenvironment. Methods: Expression of Ntn1 and its receptor Neogenin1(Neo1) were investigated in mouse models of spontaneous PDAC (LSL-Kras+/G12D/Pdx1-Cre; KC, LSL-Kras+/G12D/LSL-Trp53+/R172H/Pdx1-Cre; KPC). The influence of Ntn1 on pancreatic cancer progression and innervation was evaluated by KC mice with or without conditional knockout of Ntn1 (LSL-Kras+/G12D/Pdx1-Cre/Netrin1fl/fl; KCN). Murine PDAC cell lines and organoids were used to examine the functional role of Ntn1 and Neo1 through genetic and pharmacological modulations. The capacity of these cell lines to generate metastasis and the effect on neurite outgrowth was studied in a co-culture system with Dorsal Root Ganglia (DRG). Results: Expression of Ntn1 was not observed in normal acinar cells or ductal cells, but was found in both PanIN lesions and PDAC. Neo1 expression was similar to Ntn1 and there was a positive correlation between the expression of Ntn1 and Neo1. A lower rate of PanIN progression was observed in KCN mice compared to KC mice. In the metastatic model, overexpression of Ntn1 increased tumor burden and decreased survival while injections of a neutralizing Ntn1 antibody or genetic knockdown of Neo1 improved both endpoints. Ntn1 and Neo1 were upregulated in pancreatic organoids upon KRAS activation. Recombinant Ntn1 (rNTN1) promoted organoid forming capacity and upregulate Sox2 and Sox9 gene expression, which was inhibited by genetic knockdown of Neo1 or an anti-Neo1 antibody, supporting a direct autocrine role in modulating stemness. Nerve fibers were significantly increased at the site of PDAC liver metastasis, with Ntn1 showing the highest expression level among neurotrophins, as it was significantly increased in metastatic PDAC cells. Consistent with this observation, we observed less innervation in KCN mice, which correlated with reduced PanIN progression. Co-culture of DRGs with PDAC cells that overexpressed Ntn1 resulted in much greater axonal elongation consistent with a role of Ntn1 in promoting innervation. Conclusion: The Netrin1/Neogenin1 interaction is an important regulator of PDAC progression, acting both directly on PDAC cells to promote stemness, and indirectly via modulating tumor innervation. Blockade of Ntn1/Neo1 interaction reduces the capacity of PDAC to metastasize to the liver and improves survival. Overall, targeting the Ntn1/Neo1 interaction may represent a potential new therapeutic approach for the treatment of pancreatic cancer. Citation Format: Yosuke Ochiai, Sunagawa Masaki, Ermanno Malagola, Hiroki Kobayashi, Feijing Wu, Ruth A. White, Leah B. Zamechek, Timothy C. Wang. Netrin-1/Neogenin-1 interaction modulates pancreatic innervation to promote tumorigenesis and accelerates cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B100.
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Wang, Ligang, Lingling Zhao, Longchao Zhang, Xin Liu, Xinhua Hou, Hongmei Gao, Hua Yan, Fuping Zhao, and Lixian Wang. "NTN1 Affects Porcine Intramuscular Fat Content by Affecting the Expression of Myogenic Regulatory Factors." Animals 9, no. 9 (August 27, 2019): 609. http://dx.doi.org/10.3390/ani9090609.
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Intramuscular fat (IMF) content is an important economic trait for pork quality. Our previous results regarding the genome-wide association between IMF content and copy number variations (CNVs) indicated that the CNV within Netrin-1(NTN1-CNV) was significantly associated with IMF. In order to validate the effect of NTN1-CNV, we detected the Netrin-1 (NTN1) gene dose and protein expression content in the longissimus dorsi of different IMF content pigs using Western blotting and investigated the expression of NTN1 RNA in different tissues using real-time quantitative polymerase chain reaction (qPCR). The knock-down of the NTN1 gene in C2C12 and 3T3-L1 cells and over-expression in C2C12 cells during the proliferation and differentiation stage were also investigated to explore the possible pathway of action of NTN1. The results showed that in individuals with IMF content differences, the gene dose of NTN1 and the expression of NTN1 protein were also significantly different, which indicated that NTN1-CNV may directly affect IMF by its coding protein. NTN1 had the highest expression in pig longissimus dorsi and backfat tissues, which indicates that NTN1 may play an important role in muscle and fat tissues. The in vitro validation assay indicated that NTN1 silencing could promote the proliferation and inhibit the differentiation of C2C12 cells, with no effect on 3T3-L1 cells. Additionally, NTN1 over-expression could inhibit the proliferation and promote the differentiation of C2C12 cells. Combined with previous research, we conclude that NTN1-CNV may affect IMF by its gene dose, and the expression of NTN1 may affect the proliferation and differentiation of muscle cells by the AMP-activated protein kinase (AMPK) pathway and finally influence the IMF.
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Garcia Galindo, Jesús Jonathan, Maria G. Ramos-Zavala, Sara Pascoe-Gonzalez, Sandra O. Hernández-González, J. Santiago Delgadillo-Centeno, Fernando Grover-Páez, Alberto Beltrán-Ramírez, and Daniel O. Suarez Rico. "Association of Netrin 1 with hsCRP in Subjects with Obesity and Recent Diagnosis of Type 2 Diabetes." Current Issues in Molecular Biology 45, no. 1 (December 26, 2022): 134–40. http://dx.doi.org/10.3390/cimb45010010.
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Netrin 1 (Ntn1) is a cell migration protein with an anti-inflammatory effect, which may play a key role in the pathological development of type 2 diabetes (T2D). In this study, we evaluate the relationships between the serum concentrations of Ntn1, glucose, and high-sensitivity C-reactive Protein (hsCRP). We carried out a cross-sectional study including 90 individuals divided into three groups (n = 30): healthy subjects, individuals with obesity without glucose alterations, and individuals with newly diagnosed T2D. Serum concentrations of Ntn1 and hs-CRP were determined by enzyme-linked immunosorbent assay (ELISA). The serum concentration of Ntn1 was higher in individuals with newly diagnosed T2D (0.33 ± 0.22 ng/mL), in comparison to healthy subjects and individuals with obesity (0.13 ± 0.06 and 0.15 ± 0.07 ng/mL, respectively). In addition, we observed a positive association between the levels of Ntn1 and hsCRP (rho = 0.443; p < 0.001) as well as with serum glucose (rho = −0.110; p = 0.05). The serum concentration of Ntn1 was higher in individuals with T2D, in comparison with the other groups in this study, and presented a positive correlation with hsCRP. Therefore, Ntn1 can be considered a promising risk biomarker and a potential therapeutic target for T2D.
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Li, Dandan, Guirong Zhu, Shu Lou, Lan Ma, Chi Zhang, Yongchu Pan, and Lin Wang. "The functional variant of NTN1 contributes to the risk of nonsyndromic cleft lip with or without cleft palate." European Journal of Human Genetics 28, no. 4 (November 28, 2019): 453–60. http://dx.doi.org/10.1038/s41431-019-0549-4.
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AbstractPrevious genome-wide association study of nonsyndromic cleft lip with or without cleft palate (NSCL/P) identified a susceptible variant (rs4791774). We hypothesized that the functional single nucleotide polymorphism (SNP) may be in linkage disequilibrium with this lead SNP. The potential functional SNP (rs4791331) was identified by bioinformatic analysis. A case–control study with 891 orofacial cleft cases and 830 controls was designed to investigate its association with orofacial cleft. The allele-specific DNA-protein binding preference was predicted by JASPAR database. Cell proliferation, cycle and apoptosis, luciferase activity and netrin-1 (NTN1) expression were examined after transfection with the rs4791331 C/T vector in HEK-293 and HEPM cell lines. Forty-six lip tissues of NSCL/P patients were collected to detect NTN1 expression. ntn1a knockout zebrafish models were generated by CRISPR/Cas9 and observed with micro-CT. In the case–control study, the rs4791331-T allele was associated with an increased risk of nonsyndromic orofacial cleft (OR = 1.41, 95% CI = 1.19–1.68), as well as the subgroups cleft lip only (OR = 1.46, 95% CI = 1.14–1.87) and cleft lip and palate (OR = 1.58, 95% CI = 1.27–1.96). The T allele of rs4791331 exhibited anti-apoptotic effects and promoted cell cycle progression at the G1/S transition. Decreased enhancer activity and reduced NTN1 expression following transfection of the T allele were observed. Carriers of the CT/TT genotypes showed significantly lower expression of NTN1 than CC carriers. The ntn1a−/− zebrafish showed relatively wider intermaxillary fissures. These results indicate that rs4791331 (C > T) disrupted motif binding and led to abnormal expression of NTN1, which may be involved in the development of NSCL/P.
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Mirakaj, Valbona, Jesmond Dalli, Tiago Granja, Peter Rosenberger, and Charles N. Serhan. "Vagus nerve controls resolution and pro-resolving mediators of inflammation." Journal of Experimental Medicine 211, no. 6 (May 26, 2014): 1037–48. http://dx.doi.org/10.1084/jem.20132103.
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Resolution of inflammation is now recognized as a biosynthetically active process involving pro-resolving mediators. Here, we show in zymosan-initiated peritoneal inflammation that the vagus nerve regulates local expression of netrin-1, an axonal guidance molecule that activates resolution, and that vagotomy reduced local pro-resolving mediators, thereby delaying resolution. In netrin-1+/− mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1+/+. Netrin-1 shortened the resolution interval, decreasing exudate neutrophils, reducing proinflammatory mediators, and stimulating the production of resolvins, protectins, and lipoxins. Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins. Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other’s expression and enhanced efferocytosis. These results indicate that the vagus nerve regulates both netrin-1 and pro-resolving lipid mediators, which act in a bidirectional fashion to stimulate resolution, and provide evidence for a novel mechanism for local neuronal control of resolution.
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Mentxaka, Amaia, Javier Gómez-Ambrosi, Beatriz Ramírez, Amaia Rodríguez, Sara Becerril, Gabriela Neira, Víctor Valentí, et al. "Netrin-1 Promotes Visceral Adipose Tissue Inflammation in Obesity and Is Associated with Insulin Resistance." Nutrients 14, no. 20 (October 18, 2022): 4372. http://dx.doi.org/10.3390/nu14204372.
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Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.
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Mentxaka, Amaia, Javier Gómez-Ambrosi, Gabriela Neira, Beatriz Ramírez, Sara Becerril, Amaia Rodríguez, Víctor Valentí, et al. "Increased Expression Levels of Netrin-1 in Visceral Adipose Tissue during Obesity Favour Colon Cancer Cell Migration." Cancers 15, no. 4 (February 7, 2023): 1038. http://dx.doi.org/10.3390/cancers15041038.
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Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.
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Shiovitz, Stacey, Li Hsu, Conghui Qu, Tabitha A. Harrison, Sonja Berndt, Hermann Brenner, Graham Casey, et al. "DCC and RET pathway analysis to identify factors associated with advanced colorectal cancer." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 457. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.457.
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457 Background: DCC (deleted in colon cancer; 18q21.3) is frequently lost in colorectal cancers (CRC), but few mutations in DCC have been discovered, even in tumors with 18q loss of heterozygosity. DCC has been shown to be a dependence receptor, with differential signaling depending on the presence (proliferative) or absence (pro-apoptotic) of the netrin-1 ligand (NTN1). DCC-mutated CRC tend to present at advanced stage and have a poor prognosis. RET, another dependence receptor, is a possible tumor suppressor gene in CRC and associates with CRC progression. Given the apparent role of DCC and RET in CRC progression, we carried out a genetic association study to determine if specific genetic variants in these pathways associate with advanced vs. early CRC. Methods: Imputed HapMap genome-wide association study (GWAS) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), a collection of 19 international case-control and cohort studies, was used to identify single nucleotide polymorphisms (SNPs) in DCC, NTN1, RET and interacting genes within 5kb upstream to 500mb downstream of each of the 54 genes. With the resultant 10,102 SNPs, we performed a stage-stratified analysis, comparing advanced (AJCC stage III-IV, n = 3500) to early CRC (I-II, n = 5300). An inverse-variance weighted fixed effect meta-analysis was performed with significance set at p=0.05/10102 SNPs=5x10-6 for multiple test correction. Results: Of the examined SNPs within DCC, the lowest p-value comparing advanced vs. early CRC was 3.6x10-3. SNPs in DOCK1 (dedicator of cytokinesis 1), which complexes with DCC and netrin-1, were associated with advanced CRC at p=1.11x10-3. SNPs in NTN1 and RET reached significance only at p = 1.73x10-2 and 1.53x10-2, respectively. No SNPs reached the pre-determined level of statistical significance. Conclusions: Our current analysis does not provide clear evidence for candidate SNPs associated with advanced CRC. Further approaches include expanding the analysis to include 1,000 Genome Project and ExomeChip data (~30,000 added SNPs), comparison of cases and controls, and evaluating candidate SNP-SNP interactions to better evaluate pathway pathogenesis. We plan to present an updated analysis at the symposium.
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Harris, Chris R., Orjola Prela, Lan Wang, Anthony Casabianca, Wade Narrow, Zachary Sechrist, Tracy Withers, et al. "Abstract 1286: UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1286. http://dx.doi.org/10.1158/1538-7445.am2023-1286.
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Abstract The axonal guidance receptor UNC5B is considered to be a tumor suppressor because it promotes apoptosis in the absence of its protein ligand, NTN1. But we find that UNC5B is not a tumor suppressor of pancreatic ductal adenocarcinomas (PDAC), and instead promotes metastasis. In TCGA data, UNC5B expression associates with poor patient outcome. In vivo, pancreatic cancer metastasis was completely eliminated by knocking out UNC5B from the genetically engineered KPC mouse model of PDACs, and was reduced upon knockout of UNC5B in a splenectomy model of liver metastasis. An inhibitor of NTN1, NP137, also reduced metastasis in vivo. In vitro, knockout of UNC5B from mesenchymal pancreatic cell lines was sufficient to reduce many metastatic traits including invasiveness, EMT, and aerobic glycolysis. YAP1 is a known target of UNC5B and was overexpressed in high UNC5B expressing cell lines, which were sensitive to the YAP1 inhibitor CA3. NP137 is currently in clinical trial for several tumor types and we have been investigating which patients might respond best to this drug. Using an antibody (D9M7Z) that recognizes an epitope in UNC5B that overlaps with the caspase-3 cleavage site that is critical for UNC5B's apoptotic functions, we found two isoforms in murine and human PDACs: one isoform that contains the caspase-3-containing epitope as well as a previously-unreported isoform that to lack it. Cells expressing the caspase-3 site were much more sensitive to NP137. We also discovered genetic alterations in patient samples that induce expression of UNC5B. For instance, UNC5B was recurrently amplified in PDACs and these amplifications were highly focal to the UNC5B locus; also, UNC5B expression was increased by mutations of ARID1A, a component of the SWI/SNF transcription complex that is recurrently mutated in pancreatic adenocarcinomas. ARID1A mutations caused cell lines to become mesenchymal, but the cells returned to an epithelial phenotype upon knockout of UNC5B. In current and future clinical trials, NP137 may particularly benefit patients with tumors that harbor mutations in ARID1A or ARID1B, focal amplifications of UNC5B, and/or high expression of the caspase-3-containing isoform of UNC5B. Citation Format: Chris R. Harris, Orjola Prela, Lan Wang, Anthony Casabianca, Wade Narrow, Zachary Sechrist, Tracy Withers, Cory Shields, Asra Asad, Aram Hezel, Darren Carpizo. UNC5B promotes EMT and metastasis of pancreatic adenocarcinomas and expresses different isoforms that impact sensitivity to Netrin-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1286.
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Thams, Sebastian, Mominul Islam, Marie Lindefeldt, Ann Nordgren, Tobias Granberg, Bianca Tesi, Gisela Barbany, Daniel Nilsson, and Martin Paucar. "Heterozygous variants in DCC." Neurology Genetics 6, no. 6 (October 20, 2020): e526. http://dx.doi.org/10.1212/nxg.0000000000000526.
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ObjectiveTo perform a comprehensive characterization of a cohort of patients with congenital mirror movements (CMMs) in Sweden.MethodsClinical examination with the Woods and Teuber scale for mirror movements (MMs), neuroimaging, navigated transcranial magnetic stimulation (nTMS), and massive parallel sequencing (MPS) were applied.ResultsThe cohort is ethnically diverse and includes a total of 7 patients distributed in 2 families and 2 sporadic cases. The degree of MMs was variable in this cohort. MPS revealed 2 novel heterozygous frameshift variants in DCC netrin 1 receptor (DCC). Two siblings harboring the pathogenic variant in c.1466_1476del display a complex syndrome featuring MMs and in 1 case receptive-expressive language disorder, chorea, epilepsy, and agenesis of the corpus callosum. The second DCC variant, c.1729delG, was associated with a typical benign CMM phenotype. No variants in DCC, NTN1, RAD51, or DNAL4 were found for the 2 sporadic CMM cases. However, one of these sporadic cases had concomitant high-risk myelodysplastic syndrome and a homozygous variant in ERCC excision repair like 2 (ERCC6L2). Reorganized corticospinal projection patterns to upper extremities were demonstrated with nTMS.ConclusionsThe presence of chorea expands the clinical spectrum of syndromes associated with variants in DCC. Biallelic pathogenic variants in ERCC6L2 cause bone marrow failure, but a potential association with CMM remains to be studied in larger cohorts.
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Negussie, Mikias, Saritha Krishna, Ying Wei, Alexander Aabedi, Vardhaan Ambati, Andy Daniel, Katie Lu, and Shawn Hervey-Jumper. "CNSC-33. MOLECULAR AND FUNCTIONAL DRIVERS OF ACTIVITY DEPENDENT GLIOBLASTOMA PROLIFERATION." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v30. http://dx.doi.org/10.1093/neuonc/noad179.0117.
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Abstract Glioblastoma, the most common primary brain tumor in adults, is a major cause of neurological morbidity and mortality with no effective therapies. Its proliferation and invasion are regulated by direct and paracrine-mediated neuronal activity. In this study, we uncover molecular targets and protein-protein signaling driving activity dependent proliferation. To identify candidate molecular pathways, we used high-density electrode arrays in vivo to record human local field potentials. Single-cell RNA sequencing identified Netrin-G1 (NTNG1) and thrombospondin-1 (TSP1) elevation in glioblastoma clonal population that proliferates in response to the presence of neurons. The amino acid sequence of NTNG1 and the TSR1 domain of TSP1 were utilized to predict the 3D interaction surface of NTNG1 and TSP1. Compared to structure predictions of NTNG1 and its known binding partner NGL1, NTNG1 and TSP1 complex predictions showed agreement between machine learning predicted models and lower predicted aligned error in interdomain regions of the complex, suggesting higher confidence in the relative position of NTNG1-TSP1 as compared to NTNG1-NGL1. We performed 45 protein structure predictions and two molecular dynamics simulations of mutant and WT TSP1 in complex with NTNG1. Each simulation box consisted of >263,000 atoms, each run for 50 million 2 femtosecond timesteps for a total simulation time of 200 ns. These calculations confirmed a stable complex in the WT condition and significant conformational change in the R46A condition, emphasizing the importance of this residue in mediating NTNG1-TSP1 binding. Computational affinity models between NTNG1 and TSP1 were validated by pull-down assays and immunofluorescence labelling using cerebral organoid and human glioma-neuronal coculture models. Finally, we design small molecule and fusion-protein inhibitors disrupting this interaction. Here we advance the development of targeted precision-medicine therapies to treat glioblastoma proliferation through activity-dependent mechanisms.
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Bouilly, J., D. Cassatella, E. Elowe-Gruau, F. Phan-Hug, P. M. Bouloux, R. Quinton, and N. Pitteloud. "NTN-1 (Netrin-1)/DCC (Deleted in Colorectal Carcinoma) : nouveaux gènes impliqués dans l’hypogonadisme hypogonadotrope congénital." Annales d'Endocrinologie 77, no. 4 (September 2016): 250. http://dx.doi.org/10.1016/j.ando.2016.07.050.
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Negussie, Mikias B., Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, and Shawn L. Hervey-Jumper. "Abstract 2347: Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2347. http://dx.doi.org/10.1158/1538-7445.am2024-2347.
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Abstract Introduction Drug repurposing serves as a promising avenue for glioblastoma treatment, especially as new evidence emerges about the role of neuronal activity dependent tumor proliferation. Structure based drug discovery with virtual screening requires highly accurate 3D information about the target of choice. Recent developments in machine learning based protein structure prediction have allowed for the exploration of chemical space with virtual screening tools not previously accessible via traditional methods. Netrin-G1 (NTNG1) is an axonal guidance molecule implicated in glioblastoma with high functional connectivity to the cortex. In this study, we explore pharmacologic inhibition of NTNG1 with a clinically approved compound. Methods We perform protein structure predictions with AlphaFold2, followed by structure relaxation in an explicit solvent environment with NAMD 2.14. A final confirmation of NTNG1 was used as input to an AutoDock Vina based virtual screening platform. Zuclopenthixol (ZP) was chosen from a list of hits for microelectrode array (MEA) experiments in a mouse neuron/patient-derived tumor cell co-culture environment. Results A list of clinically approved compounds were returned from our virtual screen. ZP was chosen for validation studies, as it readily crosses the blood-brain barrier and occupies the entire TSP1 binding site in NTNG1. Preliminary results from MEA studies suggest ZP reduces tumor-mediated hyperexcitability and adequately modulates a protein-protein interaction between NTNG1 and TSP1. Conclusion By demonstrating that ZP decreases tumor-mediated hyperexcitability, this study offers evidence for the novel application of ZP to reduce glioblastoma proliferation. Further work will focus on survival analyses in mice treated with ZP and validation of experimental compounds that are structurally similar to ZP. Citation Format: Mikias B. Negussie, Saritha Krishna, Ying Wei, Cesar Nava Gonzales, Mulki Mehari, Shawn L. Hervey-Jumper. Zuclopenthixol as an inhibitor of glioblastoma-induced neuronal hyperexcitability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2347.
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"Netrin 1 (NTN1)." Science-Business eXchange 5, no. 4 (January 2012): 96. http://dx.doi.org/10.1038/scibx.2012.96.
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Cyr, Yannick, Yue Xing, Alexandra Newman, Gabrielle Pilla, Fazli Bozal, Coen van Solingen, Emily Brown, Tracy Zhang, Shruti Naik, and Kathryn J. Moore. "Abstract 572: Netrin-1 Induces Cytoskeletal-mediated Rewiring Of Mitochondrial Metabolism And Immunity." Arteriosclerosis, Thrombosis, and Vascular Biology 43, Suppl_1 (May 2023). http://dx.doi.org/10.1161/atvb.43.suppl_1.572.
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Background: Cardiometabolic diseases are characterized by maladaptive immune infiltration in metabolic tissues. This results in unresolved inflammation, mediated by macrophages (M∅). Netrin-1 (Ntn1) causes macrophage retention by inhibiting cytoskeletal activity and induces a pro-inflammatory phenotype through receptor Unc5B. Emerging evidence suggests that cellular mechanics and metabolism are reciprocally regulated, but whether this plays a role in macrophage immunometabolism has not been explored. We hypothesized that Ntn1 stimulates a cytoskeletal-mediated rewiring of cellular metabolism toward a pro-inflammatory phenotype in macrophages. Methods/Results: We report that mechanical stress stimulates Ntn1 and Unc5b expression in macrophages along with proinflammatory genes known to promote atherosclerosis. RNA-sequencing analysis comparing control (M∅ WT ) with Ntn1 -silenced macrophages (M∅ Δ Ntn1 ) under high mechanical stress revealed a transcriptional signature associated with decreased biomechanical sensing and increased energy metabolism. This was confirmed by extracellular flux assays showing higher mitochondrial respiration in M∅ Δ Ntn1 . In addition, flow cytometry and live-cell imaging showed cytoskeletal remodelling and improved mitochondrial functionality in M∅ Δ Ntn1 as measured by higher mitochondrial potential, membrane integrity and network complexity. Importantly, incubation with recombinant Ntn1 reversed the effects of genetic loss of Ntn1 , but not that of Unc5b , suggesting receptor dependency. Furthermore, as Ntn1 is tied to cytoskeletal reorganization via Rho-associated kinase (ROCK) inhibition, we tested the effects of ROCK signaling on mitochondrial metabolism. Small molecule-mediated ROCK pathway activation raised mitochondrial membrane potential in M∅ WT , mimicking loss of Ntn1 , whereas ROCK inhibition restored mitochondrial membrane potential in M∅ Δ Ntn1 to wild type level. Conclusion: Taken together, our data shows that Ntn1, through Unc5B, decreases mitochondrial function through ROCK-mediated cytoskeletal reorganization. This suggests that Ntn1 perpetuates inflammation in cardiometabolic diseases through a cytoskeletal regulation of immunometabolism in macrophages.
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Ramkhelawon, Bhama, Janine M. Van Gills, Katey J. Rayner, Sajesh Paranath, Jessica L. Feig, Edward A. Fisher, and Kathryn J. Moore. "Abstract 349: Hypoxia Induces the Expression of the Neuroimmune Guidance Cue Netrin-1 in Atherosclerotic Plaques: A Mechanism for Macrophage Retention." Arteriosclerosis, Thrombosis, and Vascular Biology 32, suppl_1 (May 2012). http://dx.doi.org/10.1161/atvb.32.suppl_1.a349.
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Hypoxia is intimately linked to atherosclerosis and promotes its progression by increasing lipid accumulation, inflammation and angiogenesis. We recently demonstrated that the neuroimmune guidance cue, netrin-1 (Ntn1) is expressed in atherosclerotic lesions where it inactivates macrophage (Mφ) migration to chemokines implicated in the egress of these inflammatory cells from plaques, including MCP-1 and CCL19. However, the mechanisms governing Ntn1 expression in atherosclerosis are not known. Immunostaining of mouse atherosclerotic plaques revealed that Ntn1 colocalized with a hypoxia probe in Mφ-rich regions of the plaque. We hypothesized that oxidative stress in the plaque provokes Ntn1 expression in Mφ, leading to local secretion of this negative regulator of Mφ migration. In vitro, stimulation of Mφ with oxidized LDL induced mRNA levels of Ntn1 and its receptor Unc5b by 3- and 6-fold respectively (p<0.01), as well as the HIF-1α target gene, Vegf (3-fold). Similarly, hypoxia mimetics such as CoCL2 (0.1 mM) and DMOG (1 mM), or exposure of Mφ to 4% O2 also upregulated Mφ expression of Ntn1 and Unc5b. Notably, these responses were abrograted by inhibiting HIF1α suggesting a causative role for this transcription factor in regulating Ntn1 and Unc5b expression in Mφ. Indeed, oxLDL-induced hypoxia increased Ntn1 and Unc5b promoter-luciferase activity by 2-5-fold, which was lost upon treatment with a HIF1α inhibitor. Furthermore, gene expression profiling of J774 macrophages overexpressing a stable form of Hif-1α (J774Hif) showed that both Ntn1 and Unc5b mRNAs were upregulated compared to control J744 cells (J774Con). Moreover, J774Hif Mφ showed reduced migration to MCP-1 compared to J774Con, consistent with the secretion of Netrin1 by these cells, and this was reversed by pretreating J774Hif with recombinant Unc5b-Fc to block the effects of Netrin1. Finally, using a bone marrow transplant model we show that targeted deletion of Ntn1 in Mφ dramatically diminishes atherosclerosis progression in Ldlr -/- mice, and promotes Mφ emigration from plaques. Together, these data suggest a causative role for hypoxia in Mφ retention and chronic inflammation in atherosclerotic lesions though its induction of this negative regulator of Mφ migration.
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Luo, Peter M., Xiaowu Gu, Christopher Chaney, Thomas Carroll, and Ondine Cleaver. "Stromal netrin-1 coordinates renal arteriogenesis and mural cell differentiation." Development, October 12, 2023. http://dx.doi.org/10.1242/dev.201884.
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The kidney vasculature has a complex architecture that is essential for renal function. The molecular mechanisms that direct development of kidney blood vessels are poorly characterized. We identified a regionally-restricted, stroma-derived signaling molecule, netrin-1 (Ntn1), as a regulator of renal vascular patterning. Stromal progenitor (SP)-specific ablation of netrin-1 (Ntn1SPKO) resulted in smaller kidneys with fewer glomeruli, as well as profound defects of the renal artery and transient blood flow disruption. Notably, Ntn1 ablation resulted in loss of arterial vascular smooth muscle cell (vSMC) coverage and in ectopic SMC deposition at the kidney surface. This was accompanied by dramatic reduction of arterial tree branching that perdured postnatally. Transcriptomic analysis of Ntn1SPKO kidneys revealed dysregulation of vSMC differentiation, including downregulation of Klf4 which we find expressed in a subset of SPs. Stromal Klf4 deletion similarly resulted in decreased smooth muscle coverage and arterial branching, however without the disruption of renal artery patterning and perfusion seen in Ntn1SPKO. These data suggest a stromal Ntn1-Klf4 axis that regulates stromal differentiation, and reinforce stromal-derived smooth muscle as a key regulator of renal blood vessel formation.
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Cline, Marcella M., Barbara Juarez, Avery Hunker, Ernesto G. Regiarto, Bryan Hariadi, Marta E. Soden, and Larry S. Zweifel. "Netrin-1 regulates the balance of synaptic glutamate signaling in the adult ventral tegmental area." eLife 12 (March 17, 2023). http://dx.doi.org/10.7554/elife.83760.
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The axonal guidance cue netrin-1 serves a critical role in neural circuit development by promoting growth cone motility, axonal branching, and synaptogenesis. Within the adult mouse brain, expression of the gene encoding (Ntn1) is highly enriched in the ventral midbrain where it is expressed in both GABAergic and dopaminergic neurons, but its function in these cell types in the adult system remains largely unknown. To address this, we performed viral-mediated, cell-type specific CRISPR-Cas9 mutagenesis of Ntn1 in the ventral tegmental area (VTA) of adult mice. Ntn1 loss-of-function in either cell type resulted in a significant reduction in excitatory postsynaptic connectivity. In dopamine neurons, the reduced excitatory tone had a minimal phenotypic behavioral outcome; however, reduced glutamatergic tone on VTA GABA neurons induced behaviors associated with a hyperdopaminergic phenotype. Simultaneous loss of Ntn1 function in both cell types largely rescued the phenotype observed in the GABA-only mutagenesis. These findings demonstrate an important role for Ntn1 in maintaining excitatory connectivity in the adult midbrain and that a balance in this connectivity within two of the major cell types of the VTA is critical for the proper functioning of the mesolimbic system.
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Huang, Huai, Tanushree Majumder, Bhakti Khot, Harindi Suriyaarachchi, Tao Yang, Qiangqiang Shao, Shraddha Tirukovalluru, and Guofa Liu. "The role of microtubule-associated protein tau in netrin-1 attractive signaling." Journal of Cell Science 137, no. 1 (January 1, 2024). http://dx.doi.org/10.1242/jcs.261244.
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ABSTRACT Direct binding of netrin receptors with dynamic microtubules (MTs) in the neuronal growth cone plays an important role in netrin-mediated axon guidance. However, how netrin-1 (NTN1) regulates MT dynamics in axon turning remains a major unanswered question. Here, we show that the coupling of netrin-1 receptor DCC with tau (MAPT)-regulated MTs is involved in netrin-1-promoted axon attraction. Tau directly interacts with DCC and partially overlaps with DCC in the growth cone of primary neurons. Netrin-1 induces this interaction and the colocalization of DCC and tau in the growth cone. The netrin-1-induced interaction of tau with DCC relies on MT dynamics and TUBB3, a highly dynamic β-tubulin isotype in developing neurons. Netrin-1 increased cosedimentation of DCC with tau and TUBB3 in MTs, and knockdown of either tau or TUBB3 mutually blocked this effect. Downregulation of endogenous tau levels by tau shRNAs inhibited netrin-1-induced axon outgrowth, branching and commissural axon attraction in vitro, and led to defects in spinal commissural axon projection in vivo. These findings suggest that tau is a key MT-associated protein coupling DCC with MT dynamics in netrin-1-promoted axon attraction.
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"Netrin 1 (NTN1); unc-5 homolog B (UNC5B; UNC5H2)." Science-Business eXchange 7, no. 12 (March 2014): 345. http://dx.doi.org/10.1038/scibx.2014.345.
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Hardy, Holly, James GD Prendergast, Aara Patel, Sunit Dutta, Violeta Trejo-Reveles, Hannah Kroeger, Andrea R. Yung, et al. "Detailed analysis of chick optic fissure closure reveals Netrin-1 as an essential mediator of epithelial fusion." eLife 8 (June 4, 2019). http://dx.doi.org/10.7554/elife.43877.
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Epithelial fusion underlies many vital organogenic processes during embryogenesis. Disruptions to these cause a significant number of human birth defects, including ocular coloboma. We provide robust spatial-temporal staging and unique anatomical detail of optic fissure closure (OFC) in the embryonic chick, including evidence for roles of apoptosis and epithelial remodelling. We performed complementary transcriptomic profiling and show that Netrin-1 (NTN1) is precisely expressed in the chick fissure margin during fusion but is immediately downregulated after fusion. We further provide a combination of protein localisation and phenotypic evidence in chick, humans, mice and zebrafish that Netrin-1 has an evolutionarily conserved and essential requirement for OFC, and is likely to have an important role in palate fusion. Our data suggest that NTN1 is a strong candidate locus for human coloboma and other multi-system developmental fusion defects, and show that chick OFC is a powerful model for epithelial fusion research.
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Cynn, Esther, Daniel Li, Marcella E. O’Reilly, Ying Wang, Alexander C. Bashore, Anjali Jha, Andrea Foulkes, et al. "Human Macrophage Long Intergenic Noncoding RNA, SIMALR , Suppresses Inflammatory Macrophage Apoptosis via NTN1 (Netrin-1)." Arteriosclerosis, Thrombosis, and Vascular Biology, December 22, 2022. http://dx.doi.org/10.1161/atvbaha.122.318353.
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Background: Long noncoding RNAs (lncRNAs) have emerged as novel regulators of macrophage biology and inflammatory cardiovascular diseases. However, studies focused on lncRNAs in human macrophage subtypes, particularly human lncRNAs that are not conserved in rodents, are limited. Methods: Through RNA-sequencing of human monocyte–derived macrophages, we identified suppressor of inflammatory macrophage apoptosis lncRNA ( SIMALR ). lipopolysaccharide/IFNγ (interferon γ) stimulated human macrophages were treated with SIMALR antisense oligonucleotides and subjected to RNA-sequencing to investigate the function of SIMALR . Western blots, luciferase assay, and RNA immunoprecipitation were performed to validate function and potential mechanism of SIMALR. RNAscope was performed to identify SIMALR expression in human carotid atherosclerotic plaques. Results: RNA-sequencing of human monocyte–derived macrophages identified SIMALR , a human macrophage-specific long intergenic noncoding RNA that is highly induced in lipopolysaccharide/IFNγ–stimulated macrophages. SIMALR knockdown in lipopolysaccharide/IFNγ stimulated THP1 human macrophages induced apoptosis of inflammatory macrophages, as shown by increased protein expression of cleaved PARP, caspase 9, caspase 3, and Annexin V+. RNA-sequencing of control versus SIMALR knockdown in lipopolysaccharide/IFNγ–stimulated macrophages showed Netrin-1 ( NTN1 ) to be significantly decreased upon SIMALR knockdown. We confirmed that NTN1 knockdown in lipopolysaccharide/IFNγ–stimulated macrophages induced apoptosis. The SIMALR knockdown-induced apoptotic phenotype was rescued by adding recombinant NTN1. NTN1 promoter-luciferase reporter activity was increased in HEK293T cells treated with lentiviral overexpression of SIMALR . NTN1 promoter activity is known to require HIF1α (hypoxia-inducible factor 1 subunit alpha), and our studies suggest that SIMALR may interact with HIF1α to regulate NTN1 transcription, thereby regulating macrophages apoptosis. SIMALR was found to be expressed in macrophages in human carotid atherosclerotic plaques of symptomatic patients. Conclusions: SIMALR is a nonconserved, human macrophage lncRNA expressed in atherosclerosis that suppresses macrophage apoptosis. SIMALR partners with HIF1α (hypoxia-inducible factor 1 subunit alpha) to regulate NTN1, which is a known macrophage survival factor. This work illustrates the importance of interrogating the functions of human lncRNAs and exploring their translational and therapeutic potential in human atherosclerosis.
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"Netrin 1 (NTN1) levels to predict invasive disease in medulloblastoma." Science-Business eXchange 7, no. 24 (June 2014): 724. http://dx.doi.org/10.1038/scibx.2014.724.
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Honeycutt, Samuel E., Pierre-Emmanuel Y. N'Guetta, Deanna M. Hardesty, Yubin Xiong, Shamus L. Cooper, Matthew J. Stevenson, and Lori L. O'Brien. "Netrin-1 directs vascular patterning and maturity in the developing kidney." Development, October 11, 2023. http://dx.doi.org/10.1242/dev.201886.
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The kidneys intricate vascular system supports body fluid and organ homeostasis. However, little is known about how vascular architecture is established during kidney development. More specifically, how signals from the kidney influence vessel maturity and patterning remains poorly understood. Netrin-1 (Ntn1) is a secreted ligand critical for vessel and neuronal guidance. Here, we demonstrate that Ntn1 is expressed by Foxd1+ stromal progenitors in the developing kidney and conditional deletion (Foxd1GC/+;Ntn1fl/fl) results in hypoplastic kidneys with extended nephrogenesis. Wholemount 3D analyses additionally revealed the loss of a predictable vascular pattern in Foxd1GC/+;Ntn1fl/fl kidneys. As vascular patterning has been linked to vessel maturity, we investigated arterialization. Quantification of the CD31+ endothelium at E15.5 revealed no differences in metrics such as the number of branches or branch points, whereas the arterial vascular smooth muscle metrics were significantly reduced at both E15.5 and P0. In support of our observed phenotypes, whole kidney RNA-seq revealed disruptions to genes and programs associated with stromal cells, vasculature, and differentiating nephrons. Together, our findings highlight the significance of netrin-1 to proper vascularization and kidney development.
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Shen, L., Y. Shen, X. Wang, and B. He. "Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation." European Heart Journal 42, Supplement_1 (October 1, 2021). http://dx.doi.org/10.1093/eurheartj/ehab724.3285.
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Abstract Aims Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and results Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E prostanoid (EP)3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. Conclusion In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy. Funding Acknowledgement Type of funding sources: None.
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"Netrin 1 (NTN1); unc-5 homolog A (Caenorhabditis elegans) (UNC5A; UNC5H1); UNC5B (UNC5H2)." Science-Business eXchange 2, no. 7 (February 2009): 269. http://dx.doi.org/10.1038/scibx.2009.269.
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"Netrin 1 (NTN1); unc-5 homolog A (UNC5A; UNC5H1); UNC5C (UNC5H3); UNC5D (UNC5H4)." Science-Business eXchange 2, no. 15 (April 2009): 616. http://dx.doi.org/10.1038/scibx.2009.616.
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Ramkhelawon, Bhama, Elizabeth J. Hennessy, Mickael Menager, Tathagat D. Ray, Frederick J. Sheedy, Susan Babunovic, George Miller, et al. "Abstract 610: Netrin-1 Promotes Macrophage Accumulation and Insulin Resistance in Obesity." Arteriosclerosis, Thrombosis, and Vascular Biology 34, suppl_1 (May 2014). http://dx.doi.org/10.1161/atvb.34.suppl_1.610.
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Obesity and its co-morbidities, type 2 diabetes and cardiovascular disease, continue to increase and are a major threat to global health. Studies in mice and humans have shown that expansion of adipose tissue mass is closely associated with the recruitment of cells of the myeloid and lymphoid lineage, which gives rise to a state of chronic inflammation that contributes to insulin resistance and type 2 diabetes. The factors that regulate the metabolic-dependent accrual of macrophages in adipose are not well understood. We show that the neuroimmune guidance cue netrin-1 is highly expressed in obese, but not lean adipose tissue of humans and mice, where it directs the retention of macrophages. In a mouse model of diet-induced obesity, we show that adipose tissue macrophages exhibit reduced migratory capacity ex vivo, which is reversed by blocking the effects of netrin-1. In vitro, expression of netrin-1 is induced in macrophages by the saturated fatty acid palmitate, and it acts by the receptor Unc5b to block macrophage migration to the chemokine CCL19, which directs the emigration of inflammatory macrophages from tissues. Using bone marrow transplantation, we show that hematopoietic deletion of Ntn1 facilitates adipose tissue macrophage emigration to the mesenteric lymph nodes, reduces inflammation, and improves insulin sensitivity and signaling in target tissues. Collectively, these findings identify netrin-1 as a macrophage retention signal that is induced in adipose tissue during obesity, which promotes chronic inflammation and insulin resistance.
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Collins Hutchinson, Meagan L., Judith St‐Onge, Sabrina Schlienger, Nassima Boudrahem‐Addour, Lina Mougharbel, Jean‐Francois Michaud, Clara Lloyd, et al. "Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals." Movement Disorders, February 5, 2024. http://dx.doi.org/10.1002/mds.29669.
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AbstractBackgroundCongenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4.ObjectiveThe aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals.MethodsWe screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin‐1 in vitro.ResultsCausal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin‐1 similarly to wild type DCC.ConclusionsA genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Meltzer, Shan, Katelyn C. Boulanger, Emmanuella Osei-Asante, Annie Handler, Qiyu Zhang, Chie Sano, Shigeyoshi Itohara, and David D. Ginty. "A role for axon–glial interactions and Netrin-G1 signaling in the formation of low-threshold mechanoreceptor end organs." Proceedings of the National Academy of Sciences 119, no. 43 (October 17, 2022). http://dx.doi.org/10.1073/pnas.2210421119.
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Low-threshold mechanoreceptors (LTMRs) and their cutaneous end organs convert light mechanical forces acting on the skin into electrical signals that propagate to the central nervous system. In mouse hairy skin, hair follicle–associated longitudinal lanceolate complexes, which are end organs comprising LTMR axonal endings that intimately associate with terminal Schwann cell (TSC) processes, mediate LTMR responses to hair deflection and skin indentation. Here, we characterized developmental steps leading to the formation of Aβ rapidly adapting (RA)-LTMR and Aδ-LTMR lanceolate complexes. During early postnatal development, Aβ RA-LTMRs and Aδ-LTMRs extend and prune cutaneous axonal branches in close association with nascent TSC processes. Netrin-G1 is expressed in these developing Aβ RA-LTMR and Aδ-LTMR lanceolate endings, and Ntng1 ablation experiments indicate that Netrin-G1 functions in sensory neurons to promote lanceolate ending elaboration around hair follicles. The Netrin-G ligand (NGL-1), encoded by Lrrc4c , is expressed in TSCs, and ablation of Lrrc4c partially phenocopied the lanceolate complex deficits observed in Ntng1 mutants. Moreover, NGL-1–Netrin-G1 signaling is a general mediator of LTMR end organ formation across diverse tissue types demonstrated by the fact that Aβ RA-LTMR endings associated with Meissner corpuscles and Pacinian corpuscles are also compromised in the Ntng1 and Lrrc4c mutant mice. Thus, axon–glia interactions, mediated in part by NGL-1–Netrin-G1 signaling, promote LTMR end organ formation.
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Xie, Yabin. "NTNG1 Modulates Progressions of Prostate Cancer Cells through JAK/STAT Signalling Pathway." INTERNATIONAL JOURNAL OF HUMAN GENETICS 22, no. 04 (September 28, 2022). http://dx.doi.org/10.31901/24566330.2022/22.04.836.
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Netrin-G1 (NTNG1) is a glycosyl-phosphatidylinositol-affixed synaptic adhesion molecule that participates in carcinoma developments. However, its underlying mechanism in regulating prostate cancer (PCa) is uncertain. NTNG1 mRNA and protein expressions in prostate cancer tissue samples and cells were demonstrated to be promoted using RT-qPCR and western blot. Thereafter, using CCK-8, NTNG1 overexpression accelerated PCa cell viability while suppressed NTNG1 restrained cell viability. Additionally, transwell results indicated that migratory and invasive abilities of PCa cells were also facilitated by overexpressed NTNG1 but inhibited with NTNG1 suppression. Furthermore, using RT-qPCR, Janus kinase 1 (JAK1) has been detected to be upregulated by NTNG1 upregulation but suppressed with NTNG1 downregulation. Moreover, JAK1, JAK2, signal transducer and activator of transcription 3 (STAT3), Ki67 and E-cadherin protein expressions were also suppressed by the knockdown of NTNG1 but elevated with NTNG1 overexpression. In PCa cells, NTNG1 acted as an oncogene through activating JAK/STAT3 signalling pathway.
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Ikegaya, Shunsuke, Yurika Iga, Sumiko Mikawa, Li Zhou, Manabu Abe, Kenji Sakimura, Kohji Sato, and Satoru Yamagishi. "Decreased Proliferation in the Neurogenic Niche, Disorganized Neuroblast Migration, and Increased Oligodendrogenesis in Adult Netrin-5-Deficient Mice." Frontiers in Neuroscience 14 (November 26, 2020). http://dx.doi.org/10.3389/fnins.2020.570974.
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In the adult mouse brain, neurogenesis occurs mainly in the ventricular-subventricular zone (V-SVZ) and the subgranular zone of the hippocampal dentate gyrus. Neuroblasts generated in the V-SVZ migrate to the olfactory bulb via the rostral migratory stream (RMS) in response to guidance molecules, such as netrin-1. We previously showed that the related netrin-5 (NTN5) is expressed in Mash1-positive transit-amplifying cells and doublecortin-positive neuroblasts in the granule cell layer of the olfactory bulb, the RMS, and the subgranular zone of the adult mouse brain. However, the precise role of NTN5 in adult neurogenesis has not been investigated. In this study, we show that proliferation in the neurogenic niche is impaired in NTN5 knockout mice. The number of proliferating (EdU-labeled) cells in NTN5 KO mice was significantly lower in the V-SVZ, whereas the number of Ki67-positive proliferating cells was unchanged, suggesting a longer cell cycle and decreased cell division in NTN5 KO mice. The number of EdU-labeled cells in the RMS and olfactory bulb was unchanged. By contrast, the numbers of EdU-labeled cells in the cortex, basal ganglia/lateral septal nucleus, and corpus callosum/anterior commissure were increased, which largely represented oligodendrocyte lineage cells. Lastly, we found that chain migration in the RMS of NTN5 KO mice was disorganized. These findings suggest that NTN5 may play important roles in promoting proliferation in the V-SVZ niche, organizing proper chain migration in the RMS, and suppressing oligodendrogenesis in the brain.