Affinage

SRY

Sex-determining region Y protein · UniProt Q05066

Length
204 aa
Mass
23.9 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SRY is the mammalian testis-determining factor, an HMG-box transcription factor that initiates the male sex-determination cascade by committing bipotential supporting-cell precursors to the Sertoli cell fate (PMID:15385158, PMID:20005972). It binds the core sequence AACAAAG in a sequence-specific manner and acts as an architectural factor that sharply bends target DNA; HMG-box point mutations found in XY females abolish DNA binding and cause XY sex reversal, establishing that this activity is required for sex determination (PMID:1734522, PMID:1425584, PMID:1339396, PMID:2247149). In a narrow ~6-hour window around 11.0–11.25 dpc in the mouse gonad, transiently expressed SRY binds a testis-specific enhancer of Sox9 (TES) cooperatively with steroidogenic factor 1 (SF1) to directly activate Sox9, driving Sertoli cell differentiation; activation outside this window fails to sustain Sox9 and yields ovarian development (PMID:19036799, PMID:20005972, PMID:15385158). The functional sex-determining transcript is a linear, genital-ridge-restricted mRNA, distinct from the predominantly cytoplasmic circular Sry RNA of adult testis, and in the mouse the active product is the two-exon SRY-T isoform, which escapes a C-terminal degron present in the single-exon form (PMID:7670499, PMID:7684656, PMID:33004521). SRY's earliest detectable effect is a Sry-dependent burst of somatic cell proliferation in the XY gonad (PMID:10654601). Sufficient Sry expression depends on upstream inputs: the WT1(+KTS) isoform acting cell-autonomously and a GADD45G→p38 MAPK→GATA4 cascade that drives GATA4 binding to the Sry promoter (PMID:19549635, PMID:23102581). SRY activity is controlled by a nuclear-transport cycle in which p300 acetylates a conserved lysine to promote importin-β-dependent nuclear import, while HDAC3 deacetylation triggers cytoplasmic relocalization (PMID:15297880). Beyond gonadal targets, SRY directly binds and activates additional promoters including MAO A (via an Sp1 complex), WDR5, Cbln4, and Sgf29, and it represses Wnt/β-catenin/TCF signaling through direct β-catenin interaction independent of its DNA-binding function, and represses androgen receptor transcriptional activity through HMG-box-mediated binding (PMID:19661285, PMID:22523547, PMID:19211811, PMID:23893245, PMID:18598779, PMID:19376480, PMID:11585838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 High

    Established that SRY is a sequence-specific, architectural DNA-binding protein whose binding activity is genetically required for sex determination, answering how a Y-linked gene could act as a master switch.

    Evidence EMSA with recombinant wild-type and HMG-box-mutant SRY, four-way-junction and DNA-bending assays, and SSCP/sequencing of XY females identifying de novo loss-of-function mutations

    PMID:1339396 PMID:1425584 PMID:1734522 PMID:2247149

    Open questions at the time
    • In vitro binding did not identify the physiological in vivo target
    • Did not establish whether SRY activates or represses transcription at native loci
  2. 1993 High

    Distinguished the functional linear sex-determining transcript from a predominantly cytoplasmic, non-polysomal circular Sry RNA in adult testis, clarifying which RNA species mediates sex determination.

    Evidence cDNA cloning, RACE, RNase protection, polysome fractionation in mouse testis; tissue/stage-specific Northern and RNase protection confirming a linear genital-ridge-restricted mRNA

    PMID:7670499 PMID:7684656

    Open questions at the time
    • Function, if any, of the circular transcript not resolved
    • Did not address regulation of the linear transcript's temporal expression
  3. 1993 Medium

    Identified candidate sex-specific promoter targets (aromatase, MIS/AMH) recognized with nanomolar affinity by the SRY HMG domain, beginning the search for direct SRY targets.

    Evidence EMSA with recombinant SRY HMG domain and embryonic urogenital ridge nuclear extracts

    PMID:8430080

    Open questions at the time
    • Direct in vivo transcriptional activation of these targets not demonstrated
    • Binding could reflect generic HMG-box recognition rather than physiological regulation
  4. 1994 Medium

    Showed that mouse Sry is a transcriptional activator with a separable Q/H-rich activation domain and nuclear localization signals, while a negative result for human SRY hinted at species differences in mechanism.

    Evidence SELEX-like site selection, reporter cotransfection, GAL4/LexA fusions, and lacZ-SRY nuclear localization assays

    PMID:7838151

    Open questions at the time
    • Human SRY transactivation in the GAL4 system was negative and unexplained
    • Single-laboratory result not independently confirmed
  5. 1996 Medium

    Proposed a potential regulatory input on SRY DNA binding through calcium-dependent calmodulin binding to the HMG box.

    Evidence Affinity chromatography, native gel, and fluorescence spectroscopy showing 1:1 CaM/HMG-box binding competed by target DNA

    PMID:8706923

    Open questions at the time
    • Physiological relevance in gonadal cells not tested
    • No in vivo evidence that CaM modulates SRY activity
  6. 2000 High

    Defined the earliest in vivo consequence of Sry expression as a Sry-dependent burst of gonadal somatic proliferation, linking the genetic switch to a cellular event.

    Evidence In vivo BrdU labeling comparing XY and XX gonads with Y-chromosome genetic controls

    PMID:10654601

    Open questions at the time
    • Molecular mediators connecting SRY to proliferation not identified
    • Relationship between proliferation and Sertoli fate commitment unresolved at this stage
  7. 2004 High

    Established that SRY is expressed transiently and exclusively in the Sertoli cell lineage and up-regulates SOX9, placing SRY action downstream of supporting-cell specification and pinpointing its developmental role.

    Evidence Transgenic lineage tracing with Sry-promoter hPLAP and Myc-tagged SRY, double immunofluorescence for SRY and SOX9

    PMID:15385158

    Open questions at the time
    • Did not demonstrate direct SRY binding to the Sox9 regulatory region
    • Transient nature of expression left timing constraints undefined
  8. 2004 High

    Revealed post-translational control of SRY localization, answering how the transient factor reaches the nucleus during its narrow activity window.

    Evidence Co-IP, in vitro/in vivo acetylation, importin-β binding, and immunofluorescence showing p300 acetylation promotes nuclear import and HDAC3 deacetylation drives cytoplasmic relocalization

    PMID:15297880

    Open questions at the time
    • Whether acetylation status changes dynamically in vivo across the sex-determining window not directly shown
    • Single laboratory
  9. 2004 Medium

    Suggested SRY recruits chromatin/repressive machinery by interacting with KRAB-O to bridge to the KAP1-HP1 complex.

    Evidence Yeast two-hybrid, GST pull-down, co-IP in COS7, and confocal colocalization in primary fetal gonadal cells

    PMID:15469996

    Open questions at the time
    • Functional consequence for any SRY target gene not demonstrated
    • Indirect (KRAB-O-bridged) association to KAP1/HP1 not reconstituted
  10. 2002 Medium

    Uncovered a non-transcriptional activity of SRY in pre-mRNA splicing mediated by its HMG domain, broadening its mechanistic repertoire.

    Evidence Live-cell colocalization with splicing factors and in vitro splicing complementation of SOX6-depleted extracts by recombinant SRY HMG domain

    PMID:11818535

    Open questions at the time
    • Physiological splicing substrates of SRY unidentified
    • Relevance to sex determination not established
  11. 2008 High

    Defined a critical ~6-hour temporal window for SRY function, showing that timely engagement of the FGF9-high/WNT4-low state is required to lock in Sox9 and the male fate.

    Evidence Heat-shock-inducible Sry transgene activated at timed intervals with analysis of Sox9, gonadal histology, and FGF9/WNT4 states

    PMID:19036799

    Open questions at the time
    • Molecular basis for the window's closure not fully resolved
    • Does not address human window timing
  12. 2008 Medium

    Showed SRY represses Wnt/β-catenin/TCF signaling through direct β-catenin binding independent of DNA-binding/transactivation, identifying a parallel anti-female-pathway activity.

    Evidence Reporter assays with active β-catenin in HEK293T, GST pull-down, β-catenin localization imaging, and patient-mutant domain mapping; corroborated for human and mouse SRY

    PMID:18598779 PMID:19376480

    Open questions at the time
    • In vivo contribution of β-catenin repression to sex determination not quantified
    • Domain requirements differ between human and mouse SRY
  13. 2001 Medium

    Identified a direct SRY–androgen receptor interaction through which SRY represses AR transcriptional activity, suggesting cross-talk with steroid signaling.

    Evidence Mammalian one/two-hybrid, GST pull-down, and reporter assays in LNCaP cells

    PMID:11585838

    Open questions at the time
    • Physiological context of SRY–AR repression unclear
    • Single laboratory, two methods
  14. 2009 High

    Provided the definitive direct mechanism for testis determination: SRY binds the Sox9 testis-specific enhancer cooperatively with SF1 to activate Sox9.

    Evidence ChIP for SRY at TES, reporter assays, and genetic epistasis in transgenic/knockout mice

    PMID:20005972

    Open questions at the time
    • Stoichiometry and structure of the SRY/SF1 enhancer complex not resolved
    • Human enhancer cooperativity not directly tested here
  15. 2009 Medium

    Expanded the direct SRY target repertoire beyond the gonad (MAO A via an Sp1 complex, Cbln4) and into co-regulatory partners, indicating broader transcriptional roles.

    Evidence EMSA, ChIP, co-IP, reporter and MAO A catalytic assays in neuroblastoma cells; ChIP and ectopic-expression for Cbln4 in vivo

    PMID:19211811 PMID:19661285

    Open questions at the time
    • Physiological significance of neuronal MAO A regulation by SRY not established
    • Single laboratory per target
  16. 2009 High

    Placed WT1(+KTS) cell-autonomously upstream of SRY and SRY upstream of FGF9/Sertoli differentiation, building the regulatory hierarchy around SRY.

    Evidence Wt1(+KTS)-null XY gonad analysis with proliferation and marker readouts plus ex vivo FGF9 rescue

    PMID:19549635

    Open questions at the time
    • Direct mechanism by which WT1(+KTS) elevates SRY per cell not defined
    • Does not address whether SRY directly activates Fgf9
  17. 2012 High

    Defined the signaling pathway ensuring sufficient and timely Sry expression, distinguishing a signaling/transcription-factor defect from epigenetic silencing.

    Evidence Gadd45g knockout mice, genetic epistasis, p38 MAPK analysis, GATA4 ChIP on the Sry promoter, and promoter methylation/histone-mark analysis

    PMID:23102581

    Open questions at the time
    • How GADD45G is itself triggered in pre-Sertoli cells not addressed
    • Conservation of the cascade in humans not tested
  18. 2012 Medium

    Identified WDR5 as a direct SRY target and SRY interactor whose complex with SRY both activates Sox9 and represses β-catenin, integrating SRY's dual activating/repressing outputs.

    Evidence EMSA, ChIP, inducible SRY expression, co-IP, colocalization, and reporter assays

    PMID:22523547

    Open questions at the time
    • In vivo requirement of WDR5 for SRY-driven Sox9 activation not shown
    • Single laboratory
  19. 2013 Medium

    Revealed an oncogenic SRY function in male hepatocellular carcinoma through direct activation of the SAGA component Sgf29.

    Evidence Luciferase reporter, ChIP, Sry knockdown/overexpression, and anchorage-independent growth/tumorigenicity assays

    PMID:23893245

    Open questions at the time
    • Relevance to human SRY in cancer not established
    • Mechanism linking Sgf29 to transformation incomplete
  20. 2020 High

    Redefined the bona fide mouse testis-determining product as the two-exon SRY-T isoform, explaining why the protein accumulates: SRY-T lacks a C-terminal degron present in the single-exon form.

    Evidence Cryptic-exon identification, Sry-T knockout and XX overexpression transgenics, and Western/protein-stability analysis

    PMID:33004521

    Open questions at the time
    • Whether an analogous isoform/degron mechanism operates in humans not established
    • Targets specifically requiring SRY-T versus SRY-S not enumerated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SRY achieves target specificity in vivo despite generic HMG-box DNA recognition, and how its activating versus repressing outputs are coordinated within the brief activity window, remain unresolved.
  • No structural model of the SRY/SF1/enhancer complex on Sox9 TES
  • Mechanism partitioning SRY between transcription, β-catenin repression, and splicing roles unknown
  • Human counterparts of the mouse SRY-T degron mechanism and GADD45G cascade untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 7 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1474165 Reproduction 2
Partners
ARCTNNB1EP300HDAC3KRAB-OSF1SP1WDR5
Complex memberships
KRAB-KAP1-HP1 complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Recombinant SRY protein binds the core DNA sequence AACAAAG in a sequence-dependent manner. Point mutations in the HMG box found in XY females abolished or reduced DNA binding activity in vitro, establishing that the DNA-binding activity of SRY is required for sex determination. In vitro DNA binding assay (gel retardation/EMSA) with recombinant wild-type and mutant SRY proteins; mutational analysis of HMG box in XY females Science High 1734522
1992 The HMG box of SRY recognizes four-way junction DNAs in a sequence-independent manner, and when SRY binds linear duplex DNA containing its specific target AACAAAG, it produces a sharp bend in the DNA, indicating that SRY functions as an architectural transcription factor that remodels DNA structure. In vitro DNA binding assays with four-way junction substrates and linear duplex DNA; gel electrophoresis-based DNA bending assays The EMBO journal High 1425584
1992 De novo point mutations in the HMG box of SRY (including a nonsense mutation converting tryptophan to a stop codon, and a missense glycine-to-arginine substitution) were identified in XY females but not in their unaffected fathers, establishing that loss-of-function mutations in SRY cause XY sex reversal. SSCP analysis and DNA sequencing of SRY in XY females; paternal controls sequenced to confirm de novo status Human genetics High 1339396 2247149
1993 The adult mouse testis produces circular RNA molecules from the Sry locus as the predominant transcript; these circular RNAs are found in the cytoplasm but are not substantially associated with polysomes, indicating they are likely not efficiently translated and are distinct from the functional linear transcript in the genital ridge. cDNA cloning, 5' RACE, RNase protection, RT-PCR, oligonucleotide hybridization, RNase H digestion, polysome fractionation Cell High 7684656
1993 The SRY DNA-binding domain specifically recognizes with nanomolar affinity proximal upstream elements (SRYe) in the promoters of the sex-specific genes P450 aromatase and Müllerian inhibiting substance (MIS/AMH), and SRYe-binding activity is present in nuclear extracts from embryonic urogenital ridge at the time preceding testicular differentiation. In vitro DNA binding assay (EMSA/gel shift) with recombinant SRY HMG domain; nuclear extract binding assays from embryonic urogenital ridge Proceedings of the National Academy of Sciences of the United States of America Medium 8430080
1994 Mouse Sry is a transcriptional activator: the mouse Sry HMG box selectively binds NACAAT/AACAAT sequences in vitro; the mouse Sry gene activates transcription of reporter genes containing AACAAT binding sites; the activation function was mapped to a glutamine/histidine-rich domain separate from the HMG box DNA-binding domain; both human and mouse SRY contain nuclear localization signals. However, a GAL4–human SRY fusion did not cause transcriptional activation, suggesting species differences. Random oligonucleotide selection (SELEX-like), reporter gene cotransfection assays, GAL4 hybrid system, LexA fusion in yeast, nuclear localization assays with lacZ-SRY hybrids Molecular endocrinology Medium 7838151
1994 Purified SRY protein binds to specific DNA sequences upstream of the AMH promoter and displays DNA bending and cruciform DNA-binding activity, consistent with a role as an architectural transcription factor. Gel retardation analysis with recombinant SRY protein; cruciform DNA binding assays Molecular reproduction and development Medium 7826621
1994 Purified SRY protein binds to a specific HMG-box response element in the rat fra-1 (Fos-related antigen 1) promoter and enhances transcription of fra-1 promoter constructs in cotransfection experiments, identifying fra-1 as a candidate transcriptional target. Gel retardation assay with purified SRY; reporter gene cotransfection Proceedings of the National Academy of Sciences of the United States of America Low 8183916
1995 The Sry transcript expressed in the developing mouse genital ridge at the sex-determining stage is a linear, polyadenylated, single-exon mRNA restricted to the genital ridge and not detected in any other fetal or adult tissue, distinguishing it from the circular testis transcript and establishing its identity as the functional transcript for sex determination. RT-PCR, Northern blot, RNase protection assays with tissue-specific and stage-specific samples Nature genetics High 7670499
1996 The HMG box domain of SRY binds calmodulin (CaM) in a calcium-dependent manner, with 1:1 stoichiometry and a conformational change in SRY. The SRY/CaM complex formation is specifically inhibited by the SRY DNA-binding site AACAAT but not a mutated sequence, suggesting that CaM and DNA compete for HMG box binding and that CaM may regulate SRY DNA-binding activity. Affinity chromatography, native gel electrophoresis, fluorescence spectroscopy; peptide binding experiments FEBS letters Medium 8706923
2000 Sry expression induces a dramatic increase in somatic cell proliferation in the XY gonad, initially in the coelomic epithelium (SF1-positive cells contributing to the Sertoli cell population), with a second stage in SF1-negative cells. Both stages of proliferation are dependent on Sry and independent of X chromosome dosage or other Y-linked genes. This proliferative response begins less than 24 hours after Sry onset and is the earliest identified effect of Sry expression. BrdU incorporation to label dividing cells in vivo; comparison of XY vs. XX gonads; genetic epistasis with Y chromosome variants Development High 10654601
2001 SRY directly interacts with the androgen receptor (AR) through the AR DNA-binding domain and the SRY HMG box, as demonstrated by mammalian one- and two-hybrid experiments and GST pull-down assays. Coexpression of SRY with AR causes marked repression of AR transcriptional activity on androgen-responsive reporters. SRY protein expression is increased by the androgen-liganded AR. Mammalian one- and two-hybrid assays; GST pull-down; reporter gene cotransfection in LNCaP cells; stable SRY transfection The Journal of biological chemistry Medium 11585838
2002 SRY (and its HMG domain specifically) colocalizes with splicing factors in the nucleus and is dynamically redistributed following splicing blockage in living cells. Recombinant SRY HMG domain efficiently restores splicing activity in SOX6-depleted nuclear extracts, revealing an unexpected role for SRY in pre-mRNA splicing. Cell imaging/colocalization with splicing factor antibodies; in vitro splicing assay with nuclear extracts; antibody supershift of spliceosome; complementation with recombinant SRY HMG domain Proceedings of the National Academy of Sciences of the United States of America Medium 11818535
2004 SRY interacts with the histone acetyltransferase p300, which acetylates SRY in vitro and in vivo at a single conserved lysine residue. Acetylation promotes nuclear localization of SRY by enhancing its interaction with importin-β. Deacetylation by HDAC3 causes cytoplasmic relocalization of SRY. These modifications regulate SRY nuclear/cytoplasmic distribution during gonadal development. Co-immunoprecipitation; in vitro and in vivo acetylation assays; importin-β binding assays; subcellular localization by immunofluorescence; expression profiling of p300 and HDAC3 during gonadal development The EMBO journal High 15297880
2004 SRY (mouse) interacts directly with the KRAB-only protein KRAB-O (encoded by an alternatively spliced transcript of the Zfp208 locus), mapped to the bridge region outside the HMG box. Through KRAB-O, SRY associates indirectly with KAP1 and heterochromatin protein 1 (HP1), colocalizing in nuclear dots in gonadal cells, suggesting SRY uses the KRAB-KAP1-HP1 regulatory complex to control downstream targets. Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation in COS7 cells; indirect immunofluorescence and confocal microscopy in primary fetal gonadal cells Biology of reproduction Medium 15469996
2004 SRY is expressed transiently and exclusively in all cells fated to become Sertoli cells in the mouse gonad. SRYMYC-positive cells first appear in the gonad (not in the coelomic epithelium), then become SRYMYC/SOX9-double-positive for only a few hours before turning into SOX9-single-positive Sertoli cells. This establishes that SRY acts after the decision to become supporting (versus interstitial) cells, and its transient expression up-regulates SOX9 to determine Sertoli cell fate. Transgenic mice with Sry promoter-driven hPLAP (stable lineage reporter) and Myc-tagged SRY; immunofluorescence double labeling; lineage tracing Developmental biology High 15385158
2008 Human SRY represses beta-catenin-mediated TCF-dependent transcription. SRY interacts directly with beta-catenin in vitro, and SRY expression triggers beta-catenin localization into specific nuclear bodies. The inhibitory activity does not require SRY DNA-binding or transactivation functions (mutant SRY proteins defective in DNA-binding retained near wild-type inhibitory activity), but requires nuclear localization of SRY. Reporter gene assays in HEK293T cells with constitutively active beta-catenin; GST pull-down (in vitro interaction); immunofluorescence for beta-catenin localization; domain-mapping with patient-derived SRY mutants The international journal of biochemistry & cell biology Medium 18598779
2008 The ability of Sry to induce testis development is limited to a critical ~6-hour window around 11.0–11.25 dpc. Activation of an inducible Sry transgene after 11.3 dpc fails to maintain Sox9 activation and results in ovarian development. This window is delimited by the ability to engage the high-FGF9/low-WNT4 signaling states required for Sertoli cell establishment. Inducible transgenic mouse system (Hsp70.3 promoter-Sry); heat-shock induction at timed intervals; analysis of Sox9 expression, gonadal histology, and FGF9/WNT4 signaling states Development High 19036799
2009 SRY directly binds a testis-specific enhancer of Sox9 (TES) and activates Sox9 expression in cooperation with the nuclear receptor steroidogenic factor 1 (SF1), as established by chromatin immunoprecipitation and functional assays. This co-operative action constitutes the primary mechanism by which SRY initiates the male sex-determination cascade. Chromatin immunoprecipitation (ChIP); reporter gene assays; genetic epistasis in transgenic/knockout mice The international journal of biochemistry & cell biology (review citing primary data) High 20005972
2009 SRY activates monoamine oxidase A (MAO A) transcription by binding a functional SRY-binding site in the MAO A core promoter (validated by EMSA and ChIP) and forming a transcriptional complex with Sp1 (shown by co-immunoprecipitation and ChIP). SRY activates both MAO A promoter activity and catalytic activity in male neuroblastoma cells. EMSA; ChIP; co-immunoprecipitation; reporter gene assays; MAO A catalytic activity assay in BE(2)C cells FASEB journal Medium 19661285
2009 SRY (both human and mouse) binds directly to beta-catenin via the HMG box (human) or HMG box plus glutamine-rich domain (mouse), and represses Rspo1/Wnt/beta-catenin signaling. The repression activity varies among SRY proteins and paradoxically correlates with the presence and/or size of an acidic/glutamine-rich domain. Reporter gene cotransfection assays; GST pull-down and direct binding assays for SRY-beta-catenin interaction; domain deletion/mutation analysis Journal of genetics and genomics Medium 19376480
2009 Chromatin immunoprecipitation identified cerebellin 4 precursor (Cbln4) as a direct in vivo target gene of SRY: anti-SRY antibody precipitated the Cbln4 upstream regulatory region. Ectopic SRY up-regulation in vivo induced ectopic Cbln4 expression, and Cbln4 expression is also regulated by SOX9 in the developing gonad. Chromatin immunoprecipitation (ChIP) with anti-SRY antibody; in vivo ectopic SRY expression experiments; Sox9 gain/loss-of-function transgenic mice Biology of reproduction Medium 19211811
2012 GADD45G promotes Sry expression in gonadal somatic cells via a signaling cascade: GADD45G → p38 MAPK → GATA4 → SRY. In Gadd45g mutant mice, Sry expression is delayed and reduced; GATA4 binding to the Sry promoter in vivo is impaired and MAPK-dependent. The Sry promoter remains demethylated and carries active histone marks in mutants, placing the defect at the signaling/transcription factor level rather than epigenetic silencing. Gadd45g knockout mouse; genetic epistasis; p38 MAPK signaling analysis; ChIP for GATA4 on Sry promoter; promoter methylation analysis; histone modification ChIP Developmental cell High 23102581
2012 WDR5 is a direct transcriptional target of SRY: EMSA and ChIP assays show SRY binds the WDR5 promoter directly. Conditional SRY expression induces WDR5 transcription with enrichment of SRY on the promoter. WDR5 and SRY interact and colocalize in cells. The WDR5-SRY complex activates Sox9 expression while repressing beta-catenin. EMSA; ChIP; 4-hydroxytamoxifen-inducible SRY expression system; co-immunoprecipitation; immunofluorescence colocalization; reporter gene assay PloS one Medium 22523547
2013 Sry directly upregulates Sgf29 (a SAGA complex component) by binding HMG-box sequences in the proximal Sgf29 promoter, as demonstrated by luciferase reporter and ChIP assays. Knockdown of Sry reduces anchorage-independent growth and tumorigenicity in male rodent hepatocellular carcinoma cells, revealing an oncogenic function of Sry mediated through Sgf29. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); Sry siRNA knockdown; ectopic Sry expression; anchorage-independent growth and tumorigenicity assays Oncogene Medium 23893245
2020 Mouse Sry harbors a cryptic second exon, producing a two-exon Sry transcript (Sry-T). SRY-T protein is expressed predominantly because SRY-S (single-exon) contains a C-terminal degron absent in SRY-T. XY mice lacking Sry-T are sex-reversed, and ectopic expression of Sry-T in XX mice induces male development, establishing SRY-T as the bona fide testis-determining factor in mice. Identification of cryptic exon; transgenic mouse experiments (Sry-T knockout and XX overexpression); Western blot comparing SRY-S vs SRY-T protein levels; protein stability/degron analysis Science High 33004521
2009 WT1(+KTS) isoform regulates Sry expression cell-autonomously: XY Wt1(+KTS)-null mouse gonads show reduced SRY protein per cell and fewer SRY-expressing cells, correlating with decreased cell proliferation near the coelomic epithelium. This blocks Sertoli cell differentiation (loss of SOX9 and Fgf9), which is rescued by exogenous recombinant FGF9 ex vivo, placing WT1(+KTS) upstream of SRY, and SRY upstream of FGF9/Sertoli differentiation. Immunofluorescence; cell proliferation analysis in Wt1(+KTS)-null XY gonads; ex vivo gonad culture with recombinant FGF9; SOX9, Fgf9, and AMH expression analysis Human molecular genetics High 19549635

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Circular transcripts of the testis-determining gene Sry in adult mouse testis. Cell 957 7684656
1990 Genetic evidence equating SRY and the testis-determining factor. Nature 766 2247149
1995 Expression of Sry, the mouse sex determining gene. Development (Cambridge, England) 479 7600978
1992 SRY, like HMG1, recognizes sharp angles in DNA. The EMBO journal 401 1425584
1992 DNA binding activity of recombinant SRY from normal males and XY females. Science (New York, N.Y.) 390 1734522
1993 Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes. The EMBO journal 309 8404853
2004 SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Developmental biology 260 15385158
2000 Sry induces cell proliferation in the mouse gonad. Development (Cambridge, England) 255 10654601
2010 Sry: the master switch in mammalian sex determination. Development (Cambridge, England) 254 21062860
2010 Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology (Baltimore, Md.) 238 21254162
2008 Sex determination and SRY: down to a wink and a nudge? Trends in genetics : TIG 229 19027189
2000 SRY, SOX9, and DAX1 expression patterns during human sex determination and gonadal development. Mechanisms of development 205 10704874
1992 Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Human genetics 202 1339396
1993 SOX3 is an X-linked gene related to SRY. Human molecular genetics 185 8111369
1992 Evolution of sex determination and the Y chromosome: SRY-related sequences in marsupials. Nature 184 1406969
2008 A critical time window of Sry action in gonadal sex determination in mice. Development (Cambridge, England) 179 19036799
1999 Sry and Sox9: mammalian testis-determining genes. Cellular and molecular life sciences : CMLS 166 10412367
2003 The molecular action and regulation of the testis-determining factors, SRY (sex-determining region on the Y chromosome) and SOX9 [SRY-related high-mobility group (HMG) box 9]. Endocrine reviews 163 12920151
1995 Expression of a linear Sry transcript in the mouse genital ridge. Nature genetics 146 7670499
1993 The human SRY transcript. Human molecular genetics 140 8111368
1993 SRY recognizes conserved DNA sites in sex-specific promoters. Proceedings of the National Academy of Sciences of the United States of America 135 8430080
2005 Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-Y(DOM) sex reversal. Developmental biology 126 15680364
2016 Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochemical pharmacology 125 27133890
2021 Weight gain before and after switch from TDF to TAF in a U.S. cohort study. Journal of the International AIDS Society 124 33838004
1994 Sry is a transcriptional activator. Molecular endocrinology (Baltimore, Md.) 118 7838151
2009 The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Human molecular genetics 101 19153074
1998 Sex in the 90s: SRY and the switch to the male pathway. Annual review of physiology 101 9558474
2004 Regulation of human SRY subcellular distribution by its acetylation/deacetylation. The EMBO journal 100 15297880
2002 The rise and fall of SRY. Trends in genetics : TIG 100 12047951
2007 Mammalian sex--Origin and evolution of the Y chromosome and SRY. Seminars in cell & developmental biology 99 17400006
2014 Switching on sex: transcriptional regulation of the testis-determining gene Sry. Development (Cambridge, England) 98 24866114
1992 A familial mutation in the testis-determining gene SRY shared by both sexes. Human genetics 96 1483689
2012 GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. Developmental cell 95 23102581
2002 A direct role of SRY and SOX proteins in pre-mRNA splicing. Proceedings of the National Academy of Sciences of the United States of America 92 11818535
2007 SRY and the standoff in sex determination. Molecular endocrinology (Baltimore, Md.) 88 17666585
2009 Regulation of monoamine oxidase A by the SRY gene on the Y chromosome. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 87 19661285
2001 SRY interacts with and negatively regulates androgen receptor transcriptional activity. The Journal of biological chemistry 85 11585838
1998 Interactions between SRY and SOX genes in mammalian sex determination. BioEssays : news and reviews in molecular, cellular and developmental biology 83 9631654
2016 Sry and SoxE genes: How they participate in mammalian sex determination and gonadal development? Seminars in cell & developmental biology 80 27481580
1994 The biochemical role of SRY in sex determination. Molecular reproduction and development 80 7826621
2008 Sex determination in mammals--before and after the evolution of SRY. Cellular and molecular life sciences : CMLS 78 18581056
1995 Widespread expression of the testis-determining gene SRY in a marsupial. Nature genetics 77 7581465
2000 Cloning and characterisation of the Sry-related transcription factor gene Sox8. Nucleic acids research 76 10684944
1996 The HMG box of SRY is a calmodulin binding domain. FEBS letters 72 8706923
2008 Boys, girls and shuttling of SRY and SOX9. Trends in endocrinology and metabolism: TEM 70 18585925
2006 Sry and the hesitant beginnings of male development. Developmental biology 70 16996051
2004 Sry associates with the heterochromatin protein 1 complex by interacting with a KRAB domain protein. Biology of reproduction 69 15469996
2021 Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 66 33336698
1994 SRY protein enhances transcription of Fos-related antigen 1 promoter constructs. Proceedings of the National Academy of Sciences of the United States of America 65 8183916
1996 Characterization of ovine SRY transcript and developmental expression of genes involved in sexual differentiation. The International journal of developmental biology 64 8840189
1993 Mutational analysis of SRY in XY females. Human mutation 63 8257986
2008 Human SRY inhibits beta-catenin-mediated transcription. The international journal of biochemistry & cell biology 62 18598779
2000 Developmental profile of Sry transcripts in mouse brain. Neurogenetics 60 11085593
2009 SRY: A transcriptional activator of mammalian testis determination. The international journal of biochemistry & cell biology 59 20005972
1993 Evidence that the SRY protein is encoded by a single exon on the human Y chromosome. Genomics 58 8244390
2005 From SRY to SOX9: mammalian testis differentiation. Journal of biochemistry 57 16046443
2009 A cell-autonomous role for WT1 in regulating Sry in vivo. Human molecular genetics 53 19549635
2002 Sex with two SOX on: SRY and SOX9 in testis development. Trends in endocrinology and metabolism: TEM 50 11893523
2001 Regulation of male sexual development by Sry and Sox9. The Journal of experimental zoology 50 11555853
2007 Identification of an OCT4 and SRY regulatory module using integrated computational and experimental genomics approaches. Genome research 49 17567999
2014 Regulation of male sex determination: genital ridge formation and Sry activation in mice. Cellular and molecular life sciences : CMLS 48 25139092
2003 Turning on the male--SRY, SOX9 and sex determination in mammals. Cytogenetic and genome research 47 14684982
1999 The human SRY protein is present in fetal and adult Sertoli cells and germ cells. The International journal of developmental biology 46 10235389
2020 The mouse Sry locus harbors a cryptic exon that is essential for male sex determination. Science (New York, N.Y.) 45 33004521
2011 Sry, more than testis determination? American journal of physiology. Regulatory, integrative and comparative physiology 45 21677270
2016 Tenofovir disoproxil fumarate (TDF) vs. emtricitabine (FTC)/TDF in lamivudine resistant hepatitis B: A 5-year randomised study. Journal of hepatology 44 27545497
2009 SRY gene increases the risk of developing gonadoblastoma and/or nontumoral gonadal lesions in Turner syndrome. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 44 19188812
1995 Bovine SRY gene locus: cloning and testicular expression. Biology of reproduction 43 7538798
2009 The human and mouse sex-determining SRY genes repress the Rspol/beta-catenin signaling. Journal of genetics and genomics = Yi chuan xue bao 42 19376480
2018 Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials. HIV medicine 41 30101539
2005 Expression of SRY proteins in both normal and sex-reversed XY fetal mouse gonads. Developmental dynamics : an official publication of the American Association of Anatomists 41 15789443
2009 The cerebellin 4 precursor gene is a direct target of SRY and SOX9 in mice. Biology of reproduction 40 19211811
2015 SRY gene transferred by extracellular vesicles accelerates atherosclerosis by promotion of leucocyte adherence to endothelial cells. Clinical science (London, England : 1979) 39 25783200
2007 Genomic and expression analysis of multiple Sry loci from a single Rattus norvegicus Y chromosome. BMC genetics 39 17408480
2001 Cloning and functional analysis of the Sry-related HMG box gene, Sox18. Gene 38 11179689
2009 Review of the Y chromosome, Sry and hypertension. Steroids 37 19914267
2003 Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 37 14689056
2008 Which Sry locus is the hypertensive Y chromosome locus? Hypertension (Dallas, Tex. : 1979) 36 19075093
2005 Ontogeny and cellular localization of SRY transcripts in the human testes and its detection in spermatozoa. Reproduction (Cambridge, England) 36 16264091
2001 XX males without SRY gene and with infertility. Human reproduction (Oxford, England) 36 11278224
1996 Porcine SRY gene locus and genital ridge expression. Biology of reproduction 36 8793057
1995 The molecular genetics of Sry and its role in mammalian sex determination. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 34 8570683
2017 Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma. Cancer letters 32 28942012
2012 SRY protein function in sex determination: thinking outside the box. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 30 22161124
2001 Molecular evolution of Sry and Sox gene. Gene 30 11404013
1995 Expression of the mouse testis-determining gene Sry in male preimplantation embryos. Molecular reproduction and development 30 7766412
2014 Transient neuroprotection by SRY upregulation in dopamine cells following injury in males. Endocrinology 29 24708242
2001 Sry, Sox9 and mammalian sex determination. EXS 29 11301599
1995 Sry-negative XX sex reversal in the German shorthaired pointer dog. The Journal of heredity 29 7560873
2008 Characteristics of testicular dysgenesis syndrome and decreased expression of SRY and SOX9 in Frasier syndrome. Molecular reproduction and development 28 18271004
2003 Prenatal genotyping of RHD and SRY using maternal blood. Vox sanguinis 28 14633256
1995 The molecular biology of SRY and its role in sex determination in mammals. Reproduction, fertility, and development 28 8711208
2011 Sry-box (Sox) transcription factors in gastrointestinal physiology and disease. American journal of physiology. Gastrointestinal and liver physiology 27 21292996
2019 TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways. Hepatology international 25 31758498
2013 The male-specific factor Sry harbors an oncogenic function. Oncogene 25 23893245
1996 Analysis of the role of Amh and Fra1 in the Sry regulatory pathway. Molecular reproduction and development 24 9115712
1995 A rainbow trout SRY-type gene expressed in pituitary glands. FEBS letters 24 8543013
1994 Transcription of circular and noncircular forms of Sry in mouse testes. Molecular reproduction and development 24 7516683
2012 Synergistic effect of SRY and its direct target, WDR5, on Sox9 expression. PloS one 23 22523547
2002 Evolution of the testis-determining gene--the rise and fall of SRY. Novartis Foundation symposium 23 11990800

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