Affinage

NANOS2

Nanos homolog 2 · UniProt P60321

Round 2 corrected
Length
138 aa
Mass
15.1 kDa
Annotated
2026-04-29
118 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NANOS2 is a male germ cell-specific RNA-binding protein that maintains spermatogonial stem cells, promotes male sexual differentiation, and suppresses meiotic entry in XY germ cells. It forms a ternary complex with DND1 and the CCR4-NOT deadenylase scaffold CNOT1 via an N-terminal NIM motif, recognizing an AUKAAWU consensus in 3′UTRs of target mRNAs (including Stra8, Dazl, Rheb, and Rhox13) to accelerate their deadenylation and degradation in P-bodies (PMID:20133598, PMID:22448252, PMID:34278268, PMID:35705038). Beyond mRNA destabilization, NANOS2 suppresses mTORC1 signaling by sequestering mTOR within mRNPs and repressing Rheb, coupling post-transcriptional gene silencing to cell-cycle quiescence and stem cell self-renewal downstream of GDNF/GFRα1 niche signaling (PMID:26120033, PMID:34401671, PMID:22102605). Loss of NANOS2 causes complete spermatogonial depletion in mice, pigs, goats, and cattle while leaving somatic testis architecture intact, a phenotype exploited for surrogate sire technology via spermatogonial stem cell transplantation (PMID:12947200, PMID:32929012).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    The fundamental question of which Nanos paralogs control mammalian germ cell survival was resolved: NANOS2 loss specifically ablates spermatogonia in males, whereas NANOS3 loss depletes germ cells in both sexes, establishing NANOS2 as a male-specific germ cell maintenance factor.

    Evidence Gene knockout mice with expression analysis

    PMID:12947200

    Open questions at the time
    • Molecular mechanism of spermatogonial loss was unknown
    • Whether NANOS2 acts at the RNA level was unestablished
    • Conservation beyond mouse untested
  2. 2006 High

    Functional hierarchy among Nanos paralogs was established: NANOS2 can substitute for NANOS3 in early PGC maintenance but not vice versa, and proper translational regulation of Nanos2 mRNA via its 3′UTR is essential for normal spermatogenesis.

    Evidence Transgenic reciprocal rescue experiments in Nanos3-null mice; knock-in mice lacking native Nanos2 3′UTR

    PMID:16806845 PMID:17138666

    Open questions at the time
    • Nature of the unique NANOS2 molecular activity in males unknown
    • Upstream signals controlling NANOS2 expression unidentified
  3. 2008 High

    NANOS2 was shown to be sufficient to suppress meiosis and activate male-specific differentiation: it prevents Stra8 expression in male germ cells and, when ectopically expressed in female germ cells, blocks meiosis and induces male-type gene expression.

    Evidence Knockout and transgenic overexpression in mouse embryonic gonads with gene expression analysis

    PMID:18281459

    Open questions at the time
    • Whether meiosis suppression is direct (RNA-level) or indirect was unknown
    • Relationship to retinoic acid signaling only partially defined
  4. 2009 High

    Lineage tracing definitively established NANOS2-expressing spermatogonia as the self-renewing stem cell population: conditional deletion depleted SSC reserves while overexpression expanded undifferentiated spermatogonia.

    Evidence Lineage tracing with Nanos2-CreERT2, conditional knockout, and overexpression in mouse testes

    PMID:19745153

    Open questions at the time
    • How NANOS2 maintains stemness at the molecular level was unresolved
    • Niche signals upstream of NANOS2 were unidentified
  5. 2010 High

    The molecular mechanism was revealed as RNA-mediated: NANOS2 localizes to P-bodies, associates with the CCR4-NOT deadenylase complex, and recruits meiosis-associated mRNAs for deadenylation-dependent degradation; upstream, FGF9 induces NANOS2 while retinoic acid suppresses it.

    Evidence Co-immunoprecipitation of CCR4-NOT components, in vitro deadenylase assay, P-body immunofluorescence, pharmacological treatment of gonocytes

    PMID:20133598 PMID:20159962

    Open questions at the time
    • Direct binding site on CCR4-NOT scaffold unknown
    • RNA-binding specificity and consensus motif undetermined
    • Whether PUM2 interaction is functionally required was untested
  6. 2012 High

    Three key advances refined the mechanism: (1) the N-terminal 10 residues of NANOS2 directly bind CNOT1 and are essential for in vivo function; (2) NANOS2 acts downstream of GDNF/GFRα1 niche signaling to maintain SSCs; (3) NANOS2 post-transcriptionally represses RHOX13 during male sexual differentiation.

    Evidence Domain mutagenesis with transgenic rescue in Nanos2-null mice; genetic epistasis with Gfra1-cKO and Nanos2 overexpression; immunofluorescence in Nanos2-KO and ectopic expression

    PMID:22102605 PMID:22190708 PMID:22448252

    Open questions at the time
    • Structural basis of NIM–CNOT1 interaction unresolved
    • How RNA target specificity is achieved independently of CCR4-NOT was unclear
  7. 2013 High

    NANOS2 was shown to promote male germ cell identity independently of meiosis suppression: double knockout of Nanos2 and Stra8 still showed loss of male-specific gene expression and failure to suppress PGC-specific genes.

    Evidence Nanos2/Stra8 double knockout mice with microarray and RNA immunoprecipitation

    PMID:24183939

    Open questions at the time
    • Identity of the male-specific transcriptional program controlled by NANOS2 was only partially catalogued
    • How mitotic quiescence is maintained mechanistically was unclear
  8. 2014 High

    Structural and regulatory resolution: the crystal structure of the NIM–CNOT1 interface (solved for NANOS1, conserved across all three paralogs) revealed conserved aromatic residues inserting into a CNOT1 hydrophobic pocket; miR-34c was identified as a physiological post-transcriptional repressor of Nanos2 mRNA promoting SSC differentiation.

    Evidence X-ray crystallography of NIM–CNOT1 with mutagenesis; luciferase reporter assays with miR-34c mimics in SSCs

    PMID:24038201 PMID:24736845

    Open questions at the time
    • Structure of NANOS2 zinc finger domain with RNA or protein partners unresolved
    • In vivo significance of miR-34c regulation not confirmed by genetic loss of function
  9. 2015 High

    A dual post-transcriptional buffering model was established: NANOS2 both recruits differentiation-promoting mRNAs for translational silencing and sequesters mTOR within mRNPs to repress mTORC1, coupling mRNA fate control to growth signaling in SSCs. DND1 was identified as the RNA-specificity cofactor that loads target mRNAs into the NANOS2–CNOT complex via the NANOS2 zinc finger domain.

    Evidence mRNP isolation, polysome profiling, mTOR pathway analysis in mouse SSCs; DND1 conditional KO, Co-IP, domain mutagenesis

    PMID:26120033 PMID:26589352

    Open questions at the time
    • Whether mTOR sequestration requires catalytic deadenylation was untested
    • Full repertoire of DND1-dependent versus DND1-independent NANOS2 targets unknown
  10. 2016 High

    NANOS2 suppresses Dazl by dual mechanisms — destabilizing Dazl mRNA via its 3′UTR and antagonizing DAZL protein function — and this axis is critical for preventing precocious meiosis and maintaining P-body integrity in male germ cells.

    Evidence In vivo 3′UTR deletion of Dazl using BAC transgenics, microarray, RNA stability assays

    PMID:27072294

    Open questions at the time
    • Whether DAZL protein antagonism involves direct physical interaction was not demonstrated
    • How P-body integrity depends on Dazl suppression mechanistically was unclear
  11. 2020 High

    Cross-species conservation and translational utility were established: NANOS2 knockout in pigs, goats, and cattle phenocopies the mouse germline ablation, and NANOS2-KO males serve as functional surrogates for donor spermatogonial stem cell transplantation.

    Evidence CRISPR-Cas9 knockout in four mammalian species with SSC transplantation and fertility assays

    PMID:28071690 PMID:32929012

    Open questions at the time
    • Whether NANOS2 mechanism is identical at the molecular level in livestock species was unconfirmed
    • Long-term donor-derived fertility efficiency not fully characterized
  12. 2021 High

    Transcriptome-wide target identification revealed the AUKAAWU consensus motif in 3′UTRs as the NANOS2 binding signature, and single-cell transcriptomics pinpointed Rheb as a direct post-transcriptional target linking NANOS2 to mTORC1 suppression and G0 arrest.

    Evidence iCLIP-seq from functional knock-in tagged allele in SSC lines; single-cell RNA-seq of WT vs. Nanos2-KO testes

    PMID:34278268 PMID:34401671

    Open questions at the time
    • Structural basis of AUKAAWU recognition by NANOS2 (alone or with DND1) unresolved
    • Direct biochemical validation of Rheb mRNA destabilization incomplete
  13. 2022 High

    Reconstitution experiments clarified that NANOS2 is not merely a passive NIM-bearing adaptor: a NIM–DND1 fusion cannot replace NANOS2, demonstrating that NANOS2 performs an essential cooperative function with DND1 in target selection beyond simply bridging DND1 to CNOT1.

    Evidence Somatic cell reconstitution system with domain fusion constructs, luciferase reporters, Co-IP

    PMID:35705038

    Open questions at the time
    • Nature of the cooperative selectivity mechanism between NANOS2 and DND1 at the structural level remains undefined
    • Whether additional cofactors participate in the NANOS2–DND1 target discrimination complex is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the atomic structure of the NANOS2 zinc finger in complex with DND1 and RNA, the full catalog of DND1-dependent versus DND1-independent targets, and whether the mTOR sequestration mechanism operates through direct binding or indirect mRNP compartmentalization.
  • No structure of NANOS2 zinc finger–DND1–RNA ternary complex
  • Mechanistic basis of mTOR sequestration in mRNPs not biochemically dissected
  • In vivo significance of PUM1/PUM2 cooperation with NANOS2 not genetically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1474165 Reproduction 3 R-HSA-162582 Signal Transduction 3
Partners
CNOT1DAZLDND1MTORPUM1PUM2
Complex memberships
CCR4-NOT deadenylase complexNANOS2–DND1–CNOT1 ternary complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Mouse Nanos2 is expressed predominantly in male germ cells after their entry into the genital ridge; knockout of Nanos2 results in complete loss of spermatogonia, whereas Nanos3 knockout causes germ cell loss in both sexes, establishing distinct roles for the two paralogs in germ cell development. Gene knockout mice, expression analysis Science High 12947200
2008 NANOS2 suppresses meiosis in male germ cells by preventing expression of Stra8 (required for premeiotic DNA replication) after Cyp26b1-mediated RA metabolism decreases, and also activates a male-specific genetic program; forced expression of Nanos2 in female germ cells inhibits meiosis and induces male-type differentiation. Knockout mice, transgenic overexpression, gene expression analysis Genes & Development High 18281459
2009 NANOS2 is an RNA-binding protein essential for maintaining spermatogonial stem cells (SSCs); lineage tracing showed Nanos2-expressing undifferentiated spermatogonia self-renew and generate the entire spermatogenic lineage; conditional Nanos2 deletion depleted SSC reserves while overexpression accumulated undifferentiated stem cell-like spermatogonia. Transgenic mice, lineage tracing, conditional knockout, overexpression Science High 19745153
2010 NANOS2 localizes to P-bodies in male gonocytes and interacts with components of the CCR4-NOT deadenylation complex (identified by immunoprecipitation); the NANOS2/CCR4-NOT complex has deadenylase activity in vitro; specific mRNAs implicated in meiosis associate with NANOS2 and accumulate in its absence, indicating NANOS2-mediated recruitment to P-bodies for degradation. Immunoprecipitation, in vitro deadenylase assay, fluorescence localization, RNA co-immunoprecipitation Proceedings of the National Academy of Sciences High 20133598
2010 Retinoic acid (RA) analog AtRA downregulates NANOS2 protein levels in fetal and postnatal gonocytes while promoting meiosis; FGF9 upregulates NANOS2 in primordial germ cells and premeiotic spermatogonia and impairs meiotic entry, indicating FGF9 acts as a meiosis inhibitor through NANOS2 upregulation. NANOS2 interacts with PUM2 and colocalizes with it in ribonucleoparticle and polysomal fractions; recombinant NANOS2 binds Gata2 and Taf7l spermatogonial mRNAs. Western blot, sucrose gradient fractionation, RNA binding assay, pharmacological treatment of primary gonocytes Journal of Cell Science Medium 20159962
2006 Nanos2 function is distinct from Nanos3: transgenic Nanos2 expressed under the Oct4ΔPE promoter rescues Nanos3-null defects in both sexes, demonstrating functional redundancy for early PGC maintenance; however, Nanos3 cannot rescue Nanos2-null defects, revealing a unique function of NANOS2 in male germ cell development. Transgenic rescue experiments in Nanos3-null background, genetic epistasis Development High 17138666
2006 The nanos2 3'UTR represses translation of nanos2 mRNA in oocytes but enhances protein production in male gonads; mice lacking the nanos2 3'UTR endogenously (nanos2pA/pA) show dose-dependent spermatogenic defects through apoptosis of gonocytes, demonstrating that translational regulation via the 3'UTR is critical for normal NANOS2 protein levels and spermatogenesis. Knock-in mouse models with and without native 3'UTR, phenotypic analysis, apoptosis assays Mechanisms of Development Medium 16806845
2012 NANOS2 directly interacts with CNOT1, a scaffold component of the CCR4-NOT deadenylation complex; the first 10 amino acids (N-terminal) of NANOS2 are required for this binding. A NANOS2-ΔN10 mutant fails to rescue Nanos2-null mice, establishing that the CCR4-NOT interaction is essential for NANOS2 function in vivo. The ΔN10 mutant retains mRNA association, suggesting additional factors determine RNA-binding specificity independently of CCR4-NOT. Co-immunoprecipitation, mutagenesis, transgenic rescue in Nanos2-null mice, RNA immunoprecipitation PLoS One High 22448252
2012 NANOS2 acts downstream of GDNF/GFRα1 signaling in spermatogonial stem cells: GDNF signaling is required to maintain NANOS2 expression; Nanos2 overexpression alleviates stem cell loss caused by Gfra1 conditional knockout and suppresses precocious differentiation even in the absence of GDNF signaling, placing NANOS2 as a downstream effector of the GDNF niche signal. Conditional knockout (Gfra1-cKO), Nanos2 overexpression in Gfra1-KO background, inducible Cre-loxP Stem Cells High 22102605
2013 NANOS2 promotes male germ cell development independently of meiosis suppression: in Nanos2/Stra8 double knockout mice (where meiosis is blocked), male-specific gene expression decreased in Nanos2-null germ cells was not recovered, indicating NANOS2 plays roles in male gene expression beyond meiosis suppression. NANOS2 also maintains mitotic quiescence but is not required for its initiation. Microarray analysis revealed NANOS2 targets undifferentiated PGC-specific genes for suppression. Double knockout mice, microarray analysis, RNA immunoprecipitation Developmental Biology High 24183939
2014 miR-34c targets the 3'UTR of Nanos2 mRNA; overexpression of miR-34c in mouse spermatogonial stem cells suppresses NANOS2 protein and promotes meiosis by upregulating Stra8, linking miR-34c-mediated post-transcriptional repression of NANOS2 to SSC differentiation. Dual-luciferase reporter assay, miR-34c mimic transfection, Western blot, lentiviral in vitro co-cultivation Journal of Cellular Biochemistry Medium 24038201
2014 Crystal structure of the human Nanos1 NIM (CNOT1-interacting motif) peptide bound to CNOT1 C-terminal domain reveals that the NIM inserts conserved aromatic residues into a conserved hydrophobic pocket on CNOT1; substitution of these residues abolishes CNOT1 binding and abrogates translational repression. This structural mechanism is conserved across Nanos1-3 in vertebrates. Crystal structure (X-ray crystallography), mutagenesis, translational repression assays Genes & Development High 24736845
2014 NANOS2 and NANOS3 interact with different components of the CNOT deadenylation complex: NANOS2 binds directly to CNOT1 while NANOS3 interacts with CNOT8; this differential interaction may explain their functional redundancy and differences. P-body formation and germ cell differentiation are more severely disrupted in Nanos2/Nanos3 double-null conditions than Nanos2-null alone. Co-immunoprecipitation, transgenic mouse analysis, P-body immunofluorescence Biology Open Medium 25416063
2015 Dead end 1 (DND1) directly interacts with NANOS2 via the zinc finger domain of NANOS2 to load unique target RNAs into the CNOT complex; this interaction is essential for target specificity. Conditional deletion of DND1 causes male germ cell differentiation defects similar to Nanos2-KO. The zinc finger domain of Nanos thus functions as a protein-interacting domain for another RNA-binding protein, not solely as an RNA-binding domain. Co-immunoprecipitation, conditional knockout, RNA immunoprecipitation, domain mutagenesis EMBO Reports High 26589352
2015 Nanos2 organizes a post-transcriptional buffering system in SSCs through two mechanisms: (1) direct recruitment of differentiation-promoting mRNAs into mRNPs for translational repression, and (2) sequestration of mTOR within mRNPs to repress mTORC1, a negative regulator of SSC self-renewal. This links mRNA turnover to mTORC1 signaling through Nanos2-containing mRNPs. mRNP isolation, polysome profiling, mTOR pathway analysis, RNA immunoprecipitation, in vivo mouse genetics Developmental Cell High 26120033
2016 NANOS2 suppresses Dazl mRNA in XY germ cells by targeting its 3'UTR; removal of the Dazl 3'UTR in vivo stabilizes Dazl mRNA, elevates meiotic gene expression, causes abnormal cell cycle resumption, and impairs P-body formation—phenocopying Nanos2-KO. NANOS2 also acts as an antagonist of DAZL protein function, establishing a dual suppression mechanism (mRNA destabilization and protein antagonism). BAC transgenic system, microarray, in vivo 3'UTR deletion, RNA stability assay Nature Communications High 27072294
2017 CRISPR/Cas9-mediated knockout of NANOS2 in pigs phenocopies mouse Nanos2-KO with male-specific germline ablation while testicular architecture and somatic cell function remain normal; females and monoallelic males are fertile, confirming conserved male-specific germline role of NANOS2 in livestock. CRISPR/Cas9 genome editing, phenotypic analysis of germline ablation Scientific Reports Medium 28071690
2018 NANOS2 cooperates with PUM1/PUM2 to regulate target mRNAs; NANOS2 does not directly bind SIAH1 3'UTR RNA (unlike NANOS3), revealing paralog-specific differences in RNA-binding mode. Mechanistic differences between NANOS1, NANOS2, and NANOS3 in PUM-cooperativity were demonstrated using luciferase reporter and EMSA assays. Luciferase reporter assay, EMSA, mutagenesis Cellular and Molecular Life Sciences Medium 30269240
2020 Male mice, pigs, goats, and cattle with CRISPR-Cas9 knockout of NANOS2 are germline-ablated but structurally normal testis-wise; allogeneic spermatogonial stem cell transplantation into NANOS2-KO males leads to sustained donor-derived spermatogenesis, demonstrating that NANOS2-KO males are functionally useful as germline-ablated surrogates for SSC transplantation. CRISPR-Cas9 KO in multiple mammalian species, spermatogonial stem cell transplantation, fertility assays Proceedings of the National Academy of Sciences High 32929012
2021 Using CLIP (crosslinking and analysis of cDNAs) on a functional epitope-tagged Nanos2 allele in SSC lines, NANOS2 was found to recognize the AUKAAWU consensus motif predominantly in the 3'UTRs of target mRNAs; NANOS2 binding reduces the half-lives of target transcripts through interaction with the CCR4-NOT deadenylase complex, regulating key signaling and metabolic pathways critical for SSC maintenance. CLIP-seq (iCLIP), knock-in epitope-tagged allele, mRNA half-life measurement, Co-IP iScience High 34278268
2021 Single-cell RNA sequencing of wild-type and Nanos2-KO testes revealed that NANOS2 expression begins in mitotic germ cells and induces mitotic arrest (G0 entry); NANOS2 represses Rheb (an mTORC1 activator) and Ptma post-transcriptionally, suppressing mTORC1 activity and thereby the cell cycle in embryonic male germ cells. Single-cell RNA sequencing, Nanos2-KO comparison, post-transcriptional target identification iScience Medium 34401671
2022 NANOS2 functions as a second-layer RNA-binding protein in target recognition: NANOS2 interacts with RNA-bound DND1 and recruits the CNOT complex to target mRNAs; however, a fusion of the NANOS2 NIM (CNOT1-binding site) with DND1 is insufficient for target repression, demonstrating NANOS2 is required both for CNOT complex recruitment and for cooperating with DND1 in selecting target mRNAs—a role not replaceable by NIM-DND1 fusion alone. Somatic cell reconstitution system, luciferase reporter, domain fusion constructs, Co-IP Cell Reports High 35705038
2012 RHOX13 translation in male germ cells is suppressed by NANOS2: RHOX13 protein appears precociously in fetal male germ cells when NANOS2 is absent, and is suppressed in female germ cells when NANOS2 is ectopically induced, indicating NANOS2 post-transcriptionally represses Rhox13 mRNA translation during sexual differentiation. Nanos2-KO analysis, ectopic Nanos2 expression in female germ cells, immunofluorescence, in vitro RA treatment Biology of Reproduction Medium 22190708

Source papers

Stage 0 corpus · 118 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Conserved role of nanos proteins in germ cell development. Science (New York, N.Y.) 463 12947200
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1996 Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proceedings of the National Academy of Sciences of the United States of America 347 8577713
1999 nos-1 and nos-2, two genes related to Drosophila nanos, regulate primordial germ cell development and survival in Caenorhabditis elegans. Development (Cambridge, England) 277 10518502
2009 The RNA-binding protein NANOS2 is required to maintain murine spermatogonial stem cells. Science (New York, N.Y.) 239 19745153
2008 Nanos2 suppresses meiosis and promotes male germ cell differentiation. Genes & development 223 18281459
2005 Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 215 16129699
2002 A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet (London, England) 150 12433515
2005 NF-kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL-1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis and cartilage 146 16376111
2014 Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression. Proceedings of the National Academy of Sciences of the United States of America 144 24733928
1999 Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 134 10593859
2010 NANOS2 interacts with the CCR4-NOT deadenylation complex and leads to suppression of specific RNAs. Proceedings of the National Academy of Sciences of the United States of America 125 20133598
2010 Opposing effects of retinoic acid and FGF9 on Nanos2 expression and meiotic entry of mouse germ cells. Journal of cell science 122 20159962
2003 Conservation of a Pumilio-Nanos complex from Drosophila germ plasm to human germ cells. Development genes and evolution 119 12690449
2006 NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 116 16908860
1999 Expression of cardiac cytokines and inducible form of nitric oxide synthase (NOS2) in Trypanosoma cruzi-infected mice. Journal of molecular and cellular cardiology 111 10072717
2014 Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses. Journal of immunology (Baltimore, Md. : 1950) 110 24477906
2006 Functional redundancy among Nanos proteins and a distinct role of Nanos2 during male germ cell development. Development (Cambridge, England) 107 17138666
2015 Signaling and stress: The redox landscape in NOS2 biology. Free radical biology & medicine 103 26117324
2014 Structural basis for the Nanos-mediated recruitment of the CCR4-NOT complex and translational repression. Genes & development 98 24736845
2013 Induction and stability of human Th17 cells require endogenous NOS2 and cGMP-dependent NO signaling. The Journal of experimental medicine 96 23797095
2000 NOS-2 mediates the protective anti-inflammatory and antifibrotic effects of the Th1-inducing adjuvant, IL-12, in a Th2 model of granulomatous disease. The American journal of pathology 93 10980133
2003 Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice. American journal of physiology. Lung cellular and molecular physiology 91 12972406
2012 Analysis of meiosis regulators in human gonads: a sexually dimorphic spatio-temporal expression pattern suggests involvement of DMRT1 in meiotic entry. Molecular human reproduction 86 22899867
2008 The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. Journal of Alzheimer's disease : JAD 84 19096157
2014 miR-34c enhances mouse spermatogonial stem cells differentiation by targeting Nanos2. Journal of cellular biochemistry 83 24038201
2017 Generation of germline ablated male pigs by CRISPR/Cas9 editing of the NANOS2 gene. Scientific reports 80 28071690
2015 Dead end1 is an essential partner of NANOS2 for selective binding of target RNAs in male germ cell development. EMBO reports 77 26589352
2018 PM2.5 induces autophagy-mediated cell death via NOS2 signaling in human bronchial epithelium cells. International journal of biological sciences 74 29805307
2006 Translational repression restricts expression of the C. elegans Nanos homolog NOS-2 to the embryonic germline. Developmental biology 74 16499902
1999 Attenuated acute cardiac rejection in NOS2 -/- recipients correlates with reduced apoptosis. Circulation 74 9989972
1998 Down-regulation of cytochrome P450 mRNAs and proteins in mice lacking a functional NOS2 gene. Molecular pharmacology 74 9687568
2016 The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. Journal of neuroinflammation 72 27246103
2012 Interaction between NANOS2 and the CCR4-NOT deadenylation complex is essential for male germ cell development in mouse. PloS one 67 22448252
2017 NOS2 as an Emergent Player in Progression of Cancer. Antioxidants & redox signaling 66 28506076
2012 NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells. Stem cells (Dayton, Ohio) 63 22102605
2006 MyD88 and NOS2 are essential for toll-like receptor 4-mediated survival effect in cardiomyocytes. American journal of physiology. Heart and circulatory physiology 62 16648192
2019 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. Nature communications 60 31515488
2015 RNA Binding Protein Nanos2 Organizes Post-transcriptional Buffering System to Retain Primitive State of Mouse Spermatogonial Stem Cells. Developmental cell 59 26120033
2002 Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. American journal of physiology. Heart and circulatory physiology 59 12063268
2020 Donor-derived spermatogenesis following stem cell transplantation in sterile NANOS2 knockout males. Proceedings of the National Academy of Sciences of the United States of America 58 32929012
2014 Spermatogonial stem cell quest: nanos2, marker of a subpopulation of undifferentiated A spermatogonia in trout testis. Biology of reproduction 58 24554733
2004 Manganese potentiates lipopolysaccharide-induced expression of NOS2 in C6 glioma cells through mitochondrial-dependent activation of nuclear factor kappaB. Brain research. Molecular brain research 58 15010209
2012 NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression. International journal of cancer 56 22618808
2013 NANOS2 promotes male germ cell development independent of meiosis suppression. Developmental biology 52 24183939
2022 LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages. Nature 51 35978195
2003 Expression of nitric oxide synthases in keratinocytes after UVB irradiation. Archives of dermatological research 45 14615895
2002 Mechanisms of NOS2 regulation by Rho GTPase signaling in airway epithelial cells. American journal of physiology. Lung cellular and molecular physiology 45 12169580
2001 Type II nitric oxide synthase (NOS2) expression correlates with lymph node status in oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 45 11271626
1998 NOS2 mediates opposing effects in models of acute and chronic cardiac rejection: insights from NOS2-knockout mice. The American journal of pathology 44 9811327
1996 Molecular cloning and structural organization of the human inducible nitric oxide synthase gene (NOS2). Biochemical and biophysical research communications 44 8645258
2002 Inducible nitric oxide synthase (NOS2) expressed in septic patients is nitrated on selected tyrosine residues: implications for enzymic activity. The Biochemical journal 43 12097137
2006 Reduced nitric oxide synthase 2 (NOS2) promoter activity in the Syrian hamster renders the animal functionally deficient in NOS2 activity and unable to control an intracellular pathogen. Journal of immunology (Baltimore, Md. : 1950) 42 16622021
2009 The highly conserved NANOS2 protein: testis-specific expression and significance for the human male reproduction. Molecular human reproduction 40 19168545
2012 NOS-2 signaling and cancer therapy. IUBMB life 39 22715033
2020 Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency. The New England journal of medicine 38 31995689
2018 Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation. International journal of molecular sciences 38 30227679
2004 Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats. Ocular immunology and inflammation 38 15512981
2001 (CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy. The Journal of allergy and clinical immunology 38 11692109
1999 Inhibition of NOS-2 expression in macrophages through the inactivation of NF-kappaB by andalusol. British journal of pharmacology 38 10516639
2018 Mannan-induced Nos2 in macrophages enhances IL-17-driven psoriatic arthritis by innate lymphocytes. Science advances 37 29774240
2018 Caffeic acid phenethyl ester promotes wound healing of mice pressure ulcers affecting NF-κB, NOS2 and NRF2 expression. Life sciences 37 29864436
2013 Zinc ferrite nanoparticles activate IL-1b, NFKB1, CCL21 and NOS2 signaling to induce mitochondrial dependent intrinsic apoptotic pathway in WISH cells. Toxicology and applied pharmacology 36 24035972
2010 Function of Nanos2 in the male germ cell lineage in mice. Cellular and molecular life sciences : CMLS 36 20652721
2018 Understanding the tumour micro-environment communication network from an NOS2/COX2 perspective. British journal of pharmacology 34 30152521
2015 Role of NOS2 in pulmonary injury and repair in response to bleomycin. Free radical biology & medicine 34 26526764
2006 Effects of noradrenaline on neuronal NOS2 expression and viability. Antioxidants & redox signaling 34 16771678
2020 DNA-based fluorescent probes of NOS2 activity in live brains. Proceedings of the National Academy of Sciences of the United States of America 33 32554491
1998 Involvement of transcriptional mechanisms in the inhibition of NOS2 expression by dexamethasone in rat mesangial cells. Kidney international 33 9452998
2016 Dazl is a target RNA suppressed by mammalian NANOS2 in sexually differentiating male germ cells. Nature communications 32 27072294
2019 NOS2 inhibitor 1400W Induces Autophagic Flux and Influences Extracellular Vesicle Profile in Human Glioblastoma U87MG Cell Line. International journal of molecular sciences 31 31226744
2015 IL-6/NOS2 inflammatory signals regulate MMP-9 and MMP-2 activity and disease outcome in nasopharyngeal carcinoma patients. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 26453114
2007 Effect of insulin-like growth factor-I on Leishmania amazonensis promastigote arginase activation and reciprocal inhibition of NOS2 pathway in macrophage in vitro. Scandinavian journal of immunology 29 17635806
2007 Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model. BMC neuroscience 29 18093296
2006 Beta-amyloid-dependent expression of NOS2 in neurons: prevention by an alpha2-adrenergic antagonist. Antioxidants & redox signaling 29 16771677
1999 Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and inflammation. Journal of neurovirology 29 10190690
2014 mNos2 deletion and human NOS2 replacement in Alzheimer disease models. Journal of neuropathology and experimental neurology 28 25003233
2006 Implication of nanos2-3'UTR in the expression and function of nanos2. Mechanisms of development 28 16806845
2020 Heme oxygenase-1 inhibition promotes IFNγ- and NOS2-mediated control of Mycobacterium tuberculosis infection. Mucosal immunology 27 32862202
2017 Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage. Scientific reports 26 28150715
2012 Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration. PLoS genetics 26 22438824
2011 Nitric oxide regulates astrocyte maturation in the hippocampus: involvement of NOS2. Molecular and cellular neurosciences 26 21354308
2011 Gene deletion of nos2 protects against manganese-induced neurological dysfunction in juvenile mice. Toxicological sciences : an official journal of the Society of Toxicology 26 22174044
2014 Interaction of NANOS2 and NANOS3 with different components of the CNOT complex may contribute to the functional differences in mouse male germ cells. Biology open 25 25416063
2013 The 3'UTR of nanos2 directs enrichment in the germ cell lineage of the sea urchin. Developmental biology 25 23357540
2013 Proteomic analysis of the NOS2 interactome in human airway epithelial cells. Nitric oxide : biology and chemistry 25 23438482
2022 NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression. Proceedings of the National Academy of Sciences of the United States of America 24 35584114
2022 The Breast Cancer Protooncogenes HER2, BRCA1 and BRCA2 and Their Regulation by the iNOS/NOS2 Axis. Antioxidants (Basel, Switzerland) 23 35740092
2018 Secreted α-Klotho maintains cartilage tissue homeostasis by repressing NOS2 and ZIP8-MMP13 catabolic axis. Aging 23 29920476
2012 Single nucleotide polymorphisms in the NOS2 and NOS3 genes are associated with exhaled nitric oxide. Journal of medical genetics 23 22368302
2016 Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling. Oncotarget 22 26593252
2019 Olive oil promotes wound healing of mice pressure injuries through NOS-2 and Nrf2. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 21 30901524
2016 Macrophage NOS2 in Tumor Leukocytes. Antioxidants & redox signaling 21 27397579
2010 Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages. British journal of pharmacology 21 20649597
2004 Simultaneous abrogation of NOS-2 and COX-2 activities is lethal in partially hepatectomised mice. Journal of hepatology 20 15158332
2001 Nitric oxide synthase (NOS2) mutation in Dahl/Rapp rats decreases enzyme stability. Circulation research 20 11509447
2023 BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection. Cellular and molecular gastroenterology and hepatology 19 37820788
2020 microRNA-216a protects against human retinal microvascular endothelial cell injury in diabetic retinopathy by suppressing the NOS2/JAK/STAT axis. Experimental and molecular pathology 19 32335083
2009 Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Human genetics 19 19859740
2003 Effect of NOS2 gene deficiency on the development of autoantibody mediated arthritis and subsequent articular cartilage degeneration. The Journal of rheumatology 19 12563676
2019 Tristetraprolin targets Nos2 expression in the colonic epithelium. Scientific reports 18 31595002
2021 NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells. iScience 17 34278268
2006 Lack of association between NOS2 pentanucleotide repeat polymorphism and asthma phenotypes or exhaled nitric oxide concentration. Pediatric pulmonology 16 16703578
2021 NANOS2 suppresses the cell cycle by repressing mTORC1 activators in embryonic male germ cells. iScience 15 34401671
2018 PUM1 and PUM2 exhibit different modes of regulation for SIAH1 that involve cooperativity with NANOS paralogues. Cellular and molecular life sciences : CMLS 15 30269240
2015 IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB. International journal of molecular medicine 15 26677135
2024 Nanos2 marks precursors of somatic lineages and is required for germline formation in the sea anemone Nematostella vectensis. Science advances 14 39151009
2012 Rhox13 is translated in premeiotic germ cells in male and female mice and is regulated by NANOS2 in the male. Biology of reproduction 14 22190708
2008 Sexual development of mouse germ cells: Nanos2 promotes the male germ cell fate by suppressing the female pathway. Development, growth & differentiation 13 18430166
2022 A cooperative mechanism of target RNA selection via germ-cell-specific RNA-binding proteins NANOS2 and DND1. Cell reports 9 35705038
2023 Identification of SARS-CoV-2 PLpro and 3CLpro human proteome substrates using substrate phage display coupled with protein network analysis. The Journal of biological chemistry 5 37201587
2016 Pluripotency induction in HEK293T cells by concurrent expression of STELLA, OCT4 and NANOS2. Biochemical and biophysical research communications 2 27794480