Nkx2-5 (Csx) is an NK-2 class homeodomain transcription factor, the vertebrate ortholog of Drosophila tinman, and a central regulator of heart development. It binds NK2 elements in RNA polymerase II promoters and enhancers as a monomer or homodimer and activates cardiac genes such as Nppa, cardiac alpha-actin, myocardin, Mef2c and Id2 in combination with partner transcription factors (GATA4, TBX5, TBX20, SRF, MEF2C, HAND2, FOXH1) and coactivators; it also represses targets in a context-dependent manner, for example Nppa in the atrioventricular canal with TBX2, the pacemaker genes Hcn4 and Tbx3 at the atrial/sinoatrial border, and Bmp2/Smad1 signalling in second heart field progenitors. Loss of Nkx2-5 in mice arrests heart looping at the linear tube stage with loss of ventricular markers such as Mlc2v and embryonic death around E9.5-10. Nkx2-5 controls cardiomyocyte differentiation and proliferation, ventricle formation, trabeculation, outflow tract development through the second heart field, and dose-dependent development and postnatal maintenance of the cardiac conduction system (atrioventricular node, His-Purkinje system). Outside the heart it is required for spleen development (with Pbx1, repressing p15Ink4b) and contributes to pharyngeal endoderm and thyroid bud development. Human NKX2-5 mutations cause congenital heart disease with atrioventricular conduction block and, rarely, asplenia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12023302 Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expressio... | ACCEPT | Summary: Tbx2 and Nkx2-5 form a complex on the Nppa (ANF) T-box/NK2 element and repress Nppa in the atrioventricular canal. Reason: Direct evidence of Nkx2-5 participating in Pol II target repression; Nkx2-5 is a context-dependent activator/repressor (also represses Hcn4/Tbx3 and Bmp2). Supporting Evidence: PMID:12023302 Tbx2 formed a complex with Nkx2.5 on the ANF TBE-NKE, and was able to repress ANF promoter activity PMID:12023302 the cooperative action of Tbx2 and Nkx2.5 inhibits expression in the AVC |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | ACCEPT | Summary: Elliott et al. analysed Nkx2-5 transcriptional activity including the YRD; repression of targets is part of Nkx2-5 function. Reason: Abstract-only; curator read full text. Repression of Pol II targets by Nkx2-5 is independently well documented (PMID:17234970, PMID:12023302). Supporting Evidence: PMID:16510504 Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer of negative regulation of Pol II transcription. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Consistent with mouse repression data. Supporting Evidence: PMID:17234970 Nkx2-5 suppresses pacemaker channel gene Hcn4 and T-box transcription factor gene Tbx3 |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IGI PMID:19483677 A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to ... | ACCEPT | Summary: Nkx2-5 cooperates with the H3K36 methyltransferase Whsc1/NSD2 to regulate (repress) target genes in embryonic heart; genetic interaction. Reason: Supports Nkx2-5 participation in repression of Pol II targets with a chromatin coregulator. Supporting Evidence: PMID:19483677 Nkx2-5 in embryonic hearts, regulating the expression of their target genes PMID:19483677 The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000096 | ACCEPT | Summary: Rat-to-mouse transfer of negative regulation of Pol II transcription. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | ISO GO_REF:0000119 | ACCEPT | Summary: Human-to-mouse transfer of negative regulation of Pol II transcription. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | MODIFY | Summary: Transcription cis-regulatory region binding, transferred from human NKX2-5. Reason: Correct but less specific than the well-supported Pol II-specific child term; Nkx2-5 binds NKE sites in Pol II promoters/enhancers (Nppa, Mef2c, Id2). Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000976 transcription cis-regulatory region binding | ISO GO_REF:0000119 | MODIFY | Summary: Transcription cis-regulatory region binding, transferred from human NKX2-5. Reason: Correct but less specific than the well-supported Pol II-specific child term; Nkx2-5 binds NKE sites in Pol II promoters/enhancers (Nppa, Mef2c, Id2). Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | MODIFY | Summary: Transcription cis-regulatory region binding, transferred from human NKX2-5. Reason: Correct but less specific than the well-supported Pol II-specific child term; Nkx2-5 binds NKE sites in Pol II promoters/enhancers (Nppa, Mef2c, Id2). Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: NK-2 family members bind Pol II cis-regulatory elements in a sequence-specific manner. Reason: Phylogenetically sound; experimental support in mouse (ANF promoter NKEs). Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:8887666 Recruitment of the tinman homolog Nkx-2.5 by serum response ... | ACCEPT | Summary: Nkx-2.5 occupies the cardiac alpha-actin promoter SRE region together with SRF. Reason: Core MF; Nkx2-5 binds NK2/SRE-like sequences in Pol II promoters (also PMID:8900044). Supporting Evidence: PMID:8887666 SRF recruited Nkx-2.5 to the alpha-actin promoter PMID:8900044 DNA binding targets for Nkx-2.5 were recently shown to represent novel homeodomain binding sequences |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer of Pol II cis-regulatory region sequence-specific DNA binding. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Core MF. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISO GO_REF:0000119 | ACCEPT | Summary: Ortholog transfer of Pol II cis-regulatory region sequence-specific DNA binding. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Core MF. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog transfer of Pol II cis-regulatory region sequence-specific DNA binding. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Core MF. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: Pol II-specific DNA-binding TF activity for the NK-2 clade. Reason: Core molecular function of Nkx2-5. Supporting Evidence: PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:21379568 The cardiac transcription network modulated by Gata4, Mef2a,... | ACCEPT | Summary: Genome-wide Nkx2.5 binding in cardiomyocytes combined with knockdown and reporter assays showing activity through an Nkx2.5 binding element. Reason: Core MF; reporter assay demonstrated motif-dependent transcriptional activity. Supporting Evidence: PMID:21379568 deletion of the potential Nkx2.5 binding element (TCCACTTTCC) showed that transcriptional activity was indeed mediated through this motif PMID:21379568 We present a systems biology study integrating mRNA profiles with DNA-binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf) |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (homeobox conserved site) mapping to Pol II DNA-binding TF activity. Reason: Correct for this homeodomain TF; core MF. |
| GO:0001216 DNA-binding transcription activator activity | IEA GO_REF:0000107 | MODIFY | Summary: DNA-binding transcription activator activity (not Pol II-specific), transferred from human. Reason: Correct but the Pol II-specific child is supported (Nppa, cardiac actin, myocardin promoters). Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0001216 DNA-binding transcription activator activity | ISO GO_REF:0000119 | MODIFY | Summary: DNA-binding transcription activator activity (not Pol II-specific), transferred from human. Reason: Correct but the Pol II-specific child is supported (Nppa, cardiac actin, myocardin promoters). Proposed replacements: DNA-binding transcription activator activity, RNA polymerase II-specific Supporting Evidence: PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:15363409 Foxh1 is essential for development of the anterior heart fie... | ACCEPT | Summary: Nkx2-5 with Foxh1 activates the Mef2c AHF enhancer (Smad-dependent TGFbeta response element). Reason: Direct activation of a Pol II cardiac target. Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:19578358 miR-145 and miR-143 regulate smooth muscle cell fate and pla... | ACCEPT | Summary: miR-143/145 promoter/enhancer is a direct transcriptional target of Nkx2-5 in cardiac progenitors. Reason: Direct activation of a Pol II-transcribed target. Supporting Evidence: PMID:19578358 miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer of Pol II-specific transcription activator activity. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Consistent with mouse data. Supporting Evidence: PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISO GO_REF:0000119 | ACCEPT | Summary: Ortholog transfer of Pol II-specific transcription activator activity. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Consistent with mouse data. Supporting Evidence: PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0001570 vasculogenesis | IMP PMID:10021345 The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstre... | MARK AS OVER ANNOTATED | Summary: Nkx2-5 null embryos show poor blood vessel development and yolk sac vascular defects. Reason: Nkx2-5 is not expressed in or required by the yolk sac endothelial lineage; vascular defects in mid-gestation embryos are most plausibly secondary to cardiac failure. Nkx2-5 does not execute vasculogenesis. Supporting Evidence: PMID:10021345 Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels PMID:10021345 Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac |
| GO:0001947 heart looping | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | ACCEPT | Summary: YRD-mutant Nkx2-5 alleles disrupt cardiogenesis including looping morphogenesis. Reason: Heart looping failure is the defining Nkx2-5 null phenotype. Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0001947 heart looping | IMP PMID:7628699 Myogenic and morphogenetic defects in the heart tubes of mur... | ACCEPT | Summary: Nkx2-5 null hearts form a linear tube but fail to initiate looping. Reason: Classic loss-of-function phenotype; core developmental role. Supporting Evidence: PMID:7628699 looping morphogenesis, a critical determinant of heart form, was not initiated at the linear heart tube stage |
| GO:0001947 heart looping | IMP PMID:9192865 Homeodomain factor Nkx2-5 controls left/right asymmetric exp... | ACCEPT | Summary: Nkx2-5 null hearts do not loop and lose left-sided eHand expression. Reason: Supports a role in looping morphogenesis. Supporting Evidence: PMID:9192865 In hearts of embryos lacking the homeobox gene Nkx2-5, which do not loop, left-sided eHand expression was abolished |
| GO:0003007 heart morphogenesis | IMP PMID:11784028 The combinatorial activities of Nkx2.5 and dHAND are essenti... | ACCEPT | Summary: Nkx2.5/dHAND double mutants lack the ventricular segment. Reason: Heart morphogenesis (chamber formation) requires Nkx2-5. Supporting Evidence: PMID:11784028 Complete ventricular dysgenesis was observed in Nkx2.5(-/-)dHAND(-/-) mutants |
| GO:0003007 heart morphogenesis | IMP PMID:17234970 Molecular pathway for the localized formation of the sinoatr... | ACCEPT | Summary: Nkx2-5 enforces the atrium/SAN boundary by repressing Hcn4 and Tbx3, shaping chamber versus nodal myocardium. Reason: Heart morphogenesis (chamber/nodal patterning) is a core developmental role of Nkx2-5. Supporting Evidence: PMID:17234970 Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node |
| GO:0003148 outflow tract septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Outflow tract septum morphogenesis transferred from human NKX2-5 (conotruncal defects in patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Downstream morphogenetic outcome of SHF regulation. Supporting Evidence: PMID:17350578 feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology |
| GO:0003148 outflow tract septum morphogenesis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Outflow tract septum morphogenesis transferred from human NKX2-5 (conotruncal defects in patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Downstream morphogenetic outcome of SHF regulation. Supporting Evidence: PMID:17350578 feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology |
| GO:0003151 outflow tract morphogenesis | IGI PMID:19035347 Cooperative interaction of Nkx2.5 and Mef2c transcription fa... | KEEP AS NON CORE | Summary: Nkx2.5;Mef2c genetic interaction in heart development including outflow tract. Reason: Genuine but downstream morphogenesis. Supporting Evidence: PMID:19035347 Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c |
| GO:0003151 outflow tract morphogenesis | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | KEEP AS NON CORE | Summary: YRD-mutant chimaeras show cardiac malformations including outflow defects. Reason: OFT morphogenesis depends on Nkx2-5 in the SHF; non-core. Supporting Evidence: PMID:17350578 feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology |
| GO:0003161 cardiac conduction system development | IGI PMID:21690310 Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regula... | ACCEPT | Summary: Nkx2-5;Cdc42 compound heterozygous mice show conduction system and cardiac output defects. Reason: Conduction system development is a major dose-sensitive Nkx2-5 function. Supporting Evidence: PMID:21690310 we examined compound heterozygous mutant mice and found conduction system and cardiac output defects |
| GO:0003161 cardiac conduction system development | ISO GO_REF:0000008 | ACCEPT | Summary: MGI orthology transfer of cardiac conduction system development. Reason: Strongly supported in mouse. Supporting Evidence: PMID:15085192 We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage |
| GO:0003161 cardiac conduction system development | ISO GO_REF:0000119 | ACCEPT | Summary: Human-to-mouse transfer of cardiac conduction system development. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Supporting Evidence: PMID:15085192 We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage |
| GO:0003162 atrioventricular node development | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | ACCEPT | Summary: Perinatal Nkx2-5 deletion causes AV conduction defects; AV node primordium is absent in null embryos (PMID:15085192). Reason: Revised from KEEP_AS_NON_CORE for consistency with the human NKX2-5 review (ortholog audit 2026-10-12), which treats AV node development as a core, dosage-sensitive Nkx2-5 process. The mouse evidence is direct (absence of the AV node primordium in nulls, AV conduction defects after deletion), and AV block is the hallmark human NKX2-5 phenotype, so this specific conduction-system subprocess is accepted as core and added to the conduction-system core function. Supporting Evidence: PMID:15085192 Null mutant embryos appear to lack the primordium of the atrioventricular node |
| GO:0003166 bundle of His development | IGI PMID:17604724 A molecular pathway including Id2, Tbx5, and Nkx2-5 required... | KEEP AS NON CORE | Summary: Tbx5/Nkx2-5 compound haploinsufficiency prevents ventricular conduction system specification. Reason: Supported; specific conduction subprocess. Supporting Evidence: PMID:17604724 compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system |
| GO:0003168 Purkinje myocyte differentiation | IMP PMID:17250822 Nkx2.5 cell-autonomous gene function is required for the pos... | KEEP AS NON CORE | Summary: Nkx2.5 is cell-autonomously required for postnatal Purkinje fibre differentiation. Reason: Well supported; specific subprocess. Supporting Evidence: PMID:17250822 the formation of the peripheral conduction system is time- and dose-dependent on the transcription factor Nkx2.5 that is cell-autonomously required for the postnatal differentiation of Purkinje fibers |
| GO:0003208 cardiac ventricle morphogenesis | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | ACCEPT | Summary: YRD mutation of Nkx2-5 disrupts cardiogenesis including ventricular morphogenesis. Reason: Ventricular chamber development is a core Nkx2-5 role (Mlc2v, Irx4, eHand). Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0003211 cardiac ventricle formation | IGI PMID:19035347 Cooperative interaction of Nkx2.5 and Mef2c transcription fa... | ACCEPT | Summary: Nkx2.5;Mef2c double mutants lack a ventricle due to defective ventricular cell differentiation. Reason: Core developmental role. Supporting Evidence: PMID:19035347 ventricular hypoplasia is the result of defective ventricular cell differentiation |
| GO:0003221 right ventricular cardiac muscle tissue morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Right ventricular cardiac muscle morphogenesis transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Consistent with SHF/AHF role (PMID:15363409). Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0003221 right ventricular cardiac muscle tissue morphogenesis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Right ventricular cardiac muscle morphogenesis transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Consistent with SHF/AHF role (PMID:15363409). Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0003222 ventricular trabecula myocardium morphogenesis | IMP PMID:15109497 Nkx2-5 pathways and congenital heart disease; loss of ventri... | KEEP AS NON CORE | Summary: Ventricular-restricted Nkx2-5 knockout causes trabecular overgrowth. Reason: Supported; specific morphogenesis aspect. Supporting Evidence: PMID:15109497 loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes |
| GO:0003228 atrial cardiac muscle tissue development | IMP PMID:17234970 Molecular pathway for the localized formation of the sinoatr... | KEEP AS NON CORE | Summary: Nkx2-5 shapes atrial myocardium identity versus sinoatrial node. Reason: Supported; non-core. Supporting Evidence: PMID:17234970 Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node |
| GO:0003278 apoptotic process involved in heart morphogenesis | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | MARK AS OVER ANNOTATED | Summary: YRD-mutant Nkx2-5 analysis; apoptosis as part of heart morphogenesis. Reason: Nkx2-5 is a transcription factor and does not execute apoptosis; any change in cell death in mutant hearts is an indirect phenotype. Null myocardium shows no enhanced apoptosis (PMID:10021345). Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0003285 septum secundum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Septum secundum development transferred from human (atrial septal defects in NKX2-5 patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Downstream morphogenesis. |
| GO:0003285 septum secundum development | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Septum secundum development transferred from human (atrial septal defects in NKX2-5 patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Downstream morphogenesis. |
| GO:0003342 proepicardium development | IMP PMID:18722343 Nkx2-5- and Isl1-expressing cardiac progenitors contribute t... | KEEP AS NON CORE | Summary: Nkx2-5 knockout causes abnormal proepicardium development with reduced Wt1. Reason: Supported; non-core. Supporting Evidence: PMID:18722343 Nkx2-5 knockout resulted in abnormal proepicardial development and decreased expression of Wt1 |
| GO:0003350 pulmonary myocardium development | IMP PMID:17823370 Pitx2c and Nkx2-5 are required for the formation and identit... | KEEP AS NON CORE | Summary: Reduced Nkx2-5 switches pulmonary myocardium to a sinoatrial-like phenotype. Reason: Supported; non-core. Supporting Evidence: PMID:17823370 When Nkx2-5 protein level was lowered in a hypomorphic model, the pulmonary myocardium switched to a Cx40-negative, Hcn4-positive phenotype |
| GO:0003677 DNA binding | IDA PMID:11042197 Characterization of homo- and heterodimerization of cardiac ... | MODIFY | Summary: Nkx2.5 homeodomain binds NKE sites in the ANF promoter as monomer and dimer. Reason: Generic DNA binding; use the Pol II cis-regulatory sequence-specific term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0003677 DNA binding | IDA PMID:12297045 Hop is an unusual homeobox gene that modulates cardiac devel... | MODIFY | Summary: Hop is a direct downstream target of Nkx2-5. Reason: Abstract-only; curator-reported Nkx2-5 DNA binding (Hop promoter). Generic term; replace with Pol II cis-regulatory binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12297045 Genetic and biochemical data indicate that Hop functions directly downstream of Nkx2-5 |
| GO:0003677 DNA binding | IDA PMID:12754203 Csm, a cardiac-specific isoform of the RNA helicase Mov10l1,... | MODIFY | Summary: Nkx2.5 transactivates the Csm (Mov10l1 isoform) promoter. Reason: Generic DNA binding; replace with Pol II-specific cis-regulatory binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:12754203 transient cotransfection analysis showed that Nkx2.5 transactivates the Csm promoter |
| GO:0003677 DNA binding | IDA PMID:15363409 Foxh1 is essential for development of the anterior heart fie... | MODIFY | Summary: Nkx2-5 with Foxh1 on the Mef2c TGFbeta response element. Reason: Generic; replace with Pol II-specific cis-regulatory binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0003677 DNA binding | IDA PMID:8900044 Activation of the cardiac alpha-actin promoter depends upon ... | MODIFY | Summary: Nkx-2.5 binds novel homeodomain sequences including SRE-like elements of the cardiac alpha-actin promoter. Reason: Generic; replace with Pol II-specific cis-regulatory binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:8900044 DNA binding targets for Nkx-2.5 were recently shown to represent novel homeodomain binding sequences |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | MODIFY | Summary: Generic DNA binding from homeodomain/ortholog mappings. Reason: Correct but uninformative; Pol II cis-regulatory sequence-specific binding is supported. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0003677 DNA binding | ISO GO_REF:0000119 | MODIFY | Summary: Generic DNA binding from homeodomain/ortholog mappings. Reason: Correct but uninformative; Pol II cis-regulatory sequence-specific binding is supported. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0003682 chromatin binding | IDA PMID:19483677 A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to ... | MODIFY | Summary: Nkx2-5 associates with Whsc1/NSD2 at target genes in embryonic hearts (ChIP). Reason: TF occupancy of target regulatory regions is better captured as sequence-specific Pol II cis-regulatory region binding than generic chromatin binding. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:19483677 Nkx2-5 in embryonic hearts, regulating the expression of their target genes |
| GO:0003682 chromatin binding | IDA PMID:21379568 The cardiac transcription network modulated by Gata4, Mef2a,... | MODIFY | Summary: ChIP-chip of Nkx2.5 in cardiomyocytes. Reason: Genome-wide occupancy of regulatory elements by a sequence-specific TF; replace chromatin binding with the Pol II cis-regulatory binding term. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding Supporting Evidence: PMID:21379568 We present a systems biology study integrating mRNA profiles with DNA-binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf) |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | MODIFY | Summary: Chromatin binding transferred from human NKX2-5. Reason: As above, the sequence-specific Pol II cis-regulatory binding term is more informative. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0003682 chromatin binding | ISO GO_REF:0000008 | MODIFY | Summary: Chromatin binding transferred from human NKX2-5. Reason: As above, the sequence-specific Pol II cis-regulatory binding term is more informative. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:11572777 A murine model of Holt-Oram syndrome defines roles of the T-... | MODIFY | Summary: Cooperative transactivation of Nppa and Cx40 promoters by Tbx5 and Nkx2-5. Reason: Correct; use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:11572777 Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | MODIFY | Summary: Nkx2-5 transcriptional activity assessed for YRD mutants. Reason: Correct; use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:16510504 Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:8900044 Activation of the cardiac alpha-actin promoter depends upon ... | MODIFY | Summary: Nkx-2.5 with SRF stimulates cardiac alpha-actin promoter transcription. Reason: Correct; use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:8900044 Nkx-2.5 facilitated serum response factor (SRF) DNA-binding activity to the multiple SREs found on the cardiac alpha-actin promoter and together stimulated cardiac alpha-actin promoter dependent transcription |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000107 | MODIFY | Summary: DNA-binding TF activity transferred from ortholog. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000096 | MODIFY | Summary: DNA-binding TF activity transferred from ortholog. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000119 | MODIFY | Summary: contributes_to DNA-binding TF activity (heteromeric complexes, e.g. with TBX5) transferred from human. Reason: Nkx2-5 has intrinsic sequence-specific TF activity rather than only contributing to that of a complex; replace with the Pol II-specific TF activity term. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0003700 DNA-binding transcription factor activity | ISO GO_REF:0000119 | MODIFY | Summary: DNA-binding TF activity transferred from ortholog. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Use the Pol II-specific child. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0005515 protein binding | IPI PMID:11572777 A murine model of Holt-Oram syndrome defines roles of the T-... | MODIFY | Summary: Nkx2-5 interacts with Tbx5 and cooperatively activates Nppa/Cx40. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:11572777 Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated |
| GO:0005515 protein binding | IPI PMID:12023302 Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expressio... | MODIFY | Summary: Nkx2-5 forms a complex with Tbx2 on the Nppa TBE-NKE. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12023302 Tbx2 formed a complex with Nkx2.5 on the ANF TBE-NKE, and was able to repress ANF promoter activity |
| GO:0005515 protein binding | IPI PMID:12392994 The basic-helix-loop-helix transcription factor HAND2 direct... | MODIFY | Summary: Nkx2.5 and HAND2 interact functionally on the ANP promoter. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:12392994 HAND2 and the homeobox factor Nkx2.5 exhibit transcriptional synergy in the regulation of ANP |
| GO:0005515 protein binding | IPI PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | MODIFY | Summary: Interaction of Nkx2-5 with GATA4 reported by GATA4 mutation study (abstract focuses on GATA4-TBX5). Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Abstract-only; Nkx2-5-GATA4 interaction independently established (PMID:9584153). Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:9584153 Coimmunoprecipitation experiments demonstrate that Csx and GATA4 associate intracellularly |
| GO:0005515 protein binding | IPI PMID:12845333 GATA4 mutations cause human congenital heart defects and rev... | MODIFY | Summary: Interaction of Nkx2-5 with human TBX5 reported in the GATA4 mutation study (abstract does not mention Nkx2-5; full text not available). Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Abstract-only; Nkx2-5-Tbx5 interaction is independently well established (PMID:11572777). Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:11572777 Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated |
| GO:0005515 protein binding | IPI PMID:14550786 Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, G... | MODIFY | Summary: Tbx20 physically interacts with Nkx2-5. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:14550786 Tbx20 physically interacted with cardiac transcription factors Nkx2-5, GATA4, and GATA5, collaborating to synergistically activate cardiac gene expression |
| GO:0005515 protein binding | IPI PMID:15363409 Foxh1 is essential for development of the anterior heart fie... | MODIFY | Summary: Foxh1 physically interacts with Nkx2-5 on the Mef2c enhancer. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0005515 protein binding | IPI PMID:15542826 Jumonji represses atrial natriuretic factor gene expression ... | MODIFY | Summary: Jumonji (Jarid2) binds Nkx2.5 and represses its transcriptional activity. Reason: Protein binding is uninformative; Jarid2 acts as a corepressor of Nkx2-5. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:15542826 JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo PMID:15542826 JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4 |
| GO:0005515 protein binding | IPI PMID:16678093 The transcriptional coactivator CAMTA2 stimulates cardiac gr... | MODIFY | Summary: CAMTA2 coactivator associates with Nkx2-5 to activate Nppa. Reason: Protein binding is uninformative; CAMTA2 acts as a coactivator of Nkx2-5. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:16678093 activates the ANF gene, at least in part, by associating with the cardiac homeodomain protein Nkx2-5 |
| GO:0005515 protein binding | IPI PMID:17584735 Transcriptional repression by the T-box proteins Tbx18 and T... | MODIFY | Summary: Tbx18 interacts with Nkx2-5 and competes Tbx5-mediated activation. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:17584735 Tbx18 interacts with Gata4 and Nkx2-5 and competes Tbx5-mediated activation |
| GO:0005515 protein binding | IPI PMID:19483677 A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to ... | MODIFY | Summary: Nkx2-5 interacts with the histone methyltransferase Whsc1/NSD2 to regulate target genes. Reason: Protein binding is uninformative; NSD2 is a chromatin coregulator recruited by Nkx2-5. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:19483677 Nkx2-5 in embryonic hearts, regulating the expression of their target genes |
| GO:0005515 protein binding | IPI PMID:22192413 UTX, a histone H3-lysine 27 demethylase, acts as a critical ... | MODIFY | Summary: UTX associates with core cardiac TFs including Nkx2.5 and is recruited to cardiac enhancers. Reason: Protein binding is uninformative; UTX/UTY act as Nkx2-5 coactivators. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:22192413 UTX is recruited to cardiac-specific enhancers by associating with core cardiac transcription factors |
| GO:0005515 protein binding | IPI PMID:23028370 UTX and UTY demonstrate histone demethylase-independent func... | MODIFY | Summary: UTY co-immunoprecipitates with NKX2-5 and enhances NKX2-5-driven ANF expression. Reason: Protein binding is uninformative; UTY acts as a coactivator of Nkx2-5. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:23028370 Myc-UTY was co-immunoprecipitated by Flag-NKX2–5 |
| GO:0005515 protein binding | IPI PMID:8887666 Recruitment of the tinman homolog Nkx-2.5 by serum response ... | MODIFY | Summary: Nkx-2.5 binds SRF and is recruited by SRF to the alpha-actin promoter. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:8887666 SRF recruited Nkx-2.5 to the alpha-actin promoter PMID:8887666 Nkx-2.5 was bound to SRF in the absence of DNA in soluble protein complexes retrieved from cardiac myocyte nuclei |
| GO:0005515 protein binding | IPI PMID:9584153 The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 ph... | MODIFY | Summary: Csx/Nkx2.5 and GATA4 associate and synergistically activate Nppa. Reason: Bare protein binding is uninformative; the partner is a DNA-binding transcription factor and the interaction underlies cooperative regulation of Pol II targets. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:9584153 Coimmunoprecipitation experiments demonstrate that Csx and GATA4 associate intracellularly PMID:9584153 Coexpression of Csx and GATA4 synergistically activates ANF reporter gene expression |
| GO:0005515 protein binding | IPI PMID:9748262 Homeodomain-interacting protein kinases, a novel family of c... | MODIFY | Summary: HIPK2 interacts with NK homeoproteins and potentiates their repressor activity. Reason: Protein binding is uninformative; HIPKs act as corepressors of NK homeodomain factors. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:9748262 HIPKs localize to nuclear speckles and potentiate the repressor activities of NK homeoproteins |
| GO:0005634 nucleus | EXP PMID:19483677 A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to ... | ACCEPT | Summary: Nkx2-5 is nuclear (UniProt cites this paper for subcellular location). Reason: Consistent with TF function. Supporting Evidence: PMID:19483677 Nkx2-5 in embryonic hearts, regulating the expression of their target genes |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus for NK-2 homeodomain TFs. Reason: Correct. |
| GO:0005634 nucleus | IDA PMID:14550786 Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, G... | ACCEPT | Summary: Nuclear localization of Nkx2-5 observed in Tbx20 interaction study. Reason: Abstract-only; consistent with all other data. |
| GO:0005634 nucleus | IDA PMID:15653675 CSX/Nkx2.5 modulates differentiation of skeletal myoblasts a... | ACCEPT | Summary: Nuclear localization of NKX2.5 in C2C12 cells. Reason: Abstract-only; consistent with TF function. |
| GO:0005634 nucleus | IDA PMID:21931855 Complex SUMO-1 regulation of cardiac transcription factor Nk... | ACCEPT | Summary: SUMOylation-site mutants retain nuclear localization. Reason: Directly observed. Supporting Evidence: PMID:21931855 failed to impair Nkx2-5 transcriptional synergism with SUMO, or its nuclear localization and DNA binding |
| GO:0005634 nucleus | IDA PMID:23892084 Histone H3 lysine 9 methyltransferases, G9a and GLP are esse... | ACCEPT | Summary: Nuclear Nkx2-5 detected in cardiomyocytes (G9a/GLP study). Reason: Abstract-only; consistent with TF function. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nucleus from UniProt subcellular location / ortholog. Reason: Correct. |
| GO:0005634 nucleus | ISO GO_REF:0000119 | ACCEPT | Summary: Nucleus from UniProt subcellular location / ortholog. Reason: Correct. |
| GO:0005654 nucleoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | ISO GO_REF:0000119 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9733796 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9734323 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9734336 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9734575 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9734594 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9735428 | ACCEPT | Summary: Nucleoplasm (electronic, orthology or Reactome events in which Nkx2-5 binds target genes such as Tbx5, Mef2c, Gata6, Myocd, Nkx2-5). Reason: Consistent with nuclear TF function. |
| GO:0005667 transcription regulator complex | IDA PMID:12023302 Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expressio... | KEEP AS NON CORE | Summary: Tbx2-Nkx2.5 complex on the Nppa TBE-NKE element. Reason: Valid; Pol II transcription regulator complex (GO:0090575) would be more specific. Supporting Evidence: PMID:12023302 Tbx2 formed a complex with Nkx2.5 on the ANF TBE-NKE, and was able to repress ANF promoter activity |
| GO:0005737 cytoplasm | IDA PMID:15653675 CSX/Nkx2.5 modulates differentiation of skeletal myoblasts a... | KEEP AS NON CORE | Summary: Cytoplasmic signal for NKX2.5 reported in myoblasts overexpressing NKX2.5. Reason: Abstract-only; Nkx2-5 is predominantly nuclear and cytoplasmic signal in an overexpression context is not a site of function. |
| GO:0005829 cytosol | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Cytosol transferred from human NKX2-5. Reason: No evidence of a cytosolic function; Nkx2-5 acts in the nucleus. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000120 | MODIFY | Summary: Regulation of DNA-templated transcription (generic). Reason: Correct; use Pol II-specific regulation. Proposed replacements: regulation of transcription by RNA polymerase II |
| GO:0006355 regulation of DNA-templated transcription | ISO GO_REF:0000119 | MODIFY | Summary: Regulation of DNA-templated transcription (generic). Reason: Correct; use Pol II-specific regulation. Proposed replacements: regulation of transcription by RNA polymerase II |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA regulation of transcription by RNA polymerase II. Reason: Core process. |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:14645532 Myocardin expression is regulated by Nkx2.5, and its functio... | ACCEPT | Summary: Nkx2.5 transactivates the myocardin promoter; myocardin downregulated in nulls. Reason: Direct regulation of a Pol II target. Supporting Evidence: PMID:14645532 Transient-cotransfection analysis showed that Nkx2.5 transactivates the myocardin promoter |
| GO:0007492 endoderm development | TAS PMID:9621431 Vertebrate homologs of tinman and bagpipe: roles of the home... | KEEP AS NON CORE | Summary: Review: Nkx2-5 expressed in pharyngeal endoderm. Reason: Endodermal role (pharynx, thyroid) exists, shown with Nkx2-6 (PMID:11390666); non-core. Supporting Evidence: PMID:9621431 Gene targeting of Csx/Nkx2.5 showed that this gene is required for completion of the looping morphogenesis of the heart |
| GO:0007507 heart development | IGI PMID:11390666 Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are requir... | ACCEPT | Summary: Nkx2.5;Nkx2.6 double mutants show retarded atrial development. Reason: Heart development is the principal role of Nkx2-5. Supporting Evidence: PMID:11390666 the development of the atrium was less advanced in the double-mutant embryos, indicating that these two genes are essential for both pharyngeal and cardiac development |
| GO:0007507 heart development | IMP PMID:10021345 The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstre... | ACCEPT | Summary: Nkx2-5 null embryos arrest heart development after looping. Reason: Core. Supporting Evidence: PMID:10021345 Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels |
| GO:0007507 heart development | IMP PMID:15085192 Nkx2-5 mutation causes anatomic hypoplasia of the cardiac co... | ACCEPT | Summary: Nkx2-5 mutation causes conduction system hypoplasia. Reason: Core (heart development). Supporting Evidence: PMID:15085192 We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage |
| GO:0007507 heart development | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | ACCEPT | Summary: Nkx2-5 is central to the cardiac developmental TF network. Reason: Core. Supporting Evidence: PMID:16510504 Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development |
| GO:0007512 adult heart development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Adult heart development transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Nkx2-5 is required postnatally for conduction/contraction (PMID:19546853). Supporting Evidence: PMID:19546853 Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age |
| GO:0007512 adult heart development | IMP PMID:7628699 Myogenic and morphogenetic defects in the heart tubes of mur... | MODIFY | Summary: Nkx2-5 null embryos die at ~E9-10 with heart tube defects. Reason: The paper analyses embryonic hearts, so 'adult heart development' does not fit; the essence is heart development. Proposed replacements: heart development Supporting Evidence: PMID:7628699 The data demonstrate that Nkx2-5 is essential for normal heart morphogenesis, myogenesis, and function |
| GO:0007512 adult heart development | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Adult heart development transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:11390666 Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are requir... | KEEP AS NON CORE | Summary: Reduced proliferation of pharyngeal endoderm in Nkx2.5;Nkx2.6 double mutants. Reason: Indirect, tissue-specific; non-core. Supporting Evidence: PMID:11390666 we observed enhanced apoptosis and reduced proliferation in pharyngeal endodermal cells of the double-mutant embryos |
| GO:0009888 tissue development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA 'tissue development'. Reason: Too general to be informative; specific heart/spleen terms capture the role. |
| GO:0010628 positive regulation of gene expression | IDA PMID:9857019 Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other... | MODIFY | Summary: Nkx2-5 overexpression in P19 cells activates MEF2C expression. Reason: Positive regulation of gene expression is generic; this is transcriptional activation of a Pol II target. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:9857019 Nkx2-5 expression resulted in the activation of myocyte enhancer factor 2C (MEF2C) |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of cardiomyocyte apoptosis transferred from human/mouse data. Reason: Supported by dominant-negative and overexpression studies; non-core. Supporting Evidence: PMID:11889119 Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IMP PMID:11889119 Csx/Nkx2-5 is required for homeostasis and survival of cardi... | KEEP AS NON CORE | Summary: Dominant-negative Nkx2-5 induces cardiomyocyte apoptosis; wild-type protects against doxorubicin. Reason: Supported; non-core maintenance role. Supporting Evidence: PMID:11889119 Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Negative regulation of cardiomyocyte apoptosis transferred from human/mouse data. Reason: Supported by dominant-negative and overexpression studies; non-core. Supporting Evidence: PMID:11889119 Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death |
| GO:0010765 positive regulation of sodium ion transport | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | MARK AS OVER ANNOTATED | Summary: Perinatal Nkx2-5 deletion reduces ventricular Nav1.5 expression. Reason: Nkx2-5 regulates Scn5a expression; describing this as regulation of sodium ion transport is an indirect consequence of transcriptional control. Supporting Evidence: PMID:18689573 Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit |
| GO:0010832 negative regulation of myotube differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Negative regulation of myotube differentiation, transferred from human NKX2-5. Reason: Based on forced NKX2.5 expression in C2C12 skeletal myoblasts (PMID:15653675); not a physiological role. Supporting Evidence: PMID:15653675 The expression of human NKX2.5 in C2C12 myoblasts inhibited myocyte differentiation and myotube formation |
| GO:0010832 negative regulation of myotube differentiation | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Negative regulation of myotube differentiation, transferred from human NKX2-5. Reason: Based on forced NKX2.5 expression in C2C12 skeletal myoblasts (PMID:15653675); not a physiological role. Supporting Evidence: PMID:15653675 The expression of human NKX2.5 in C2C12 myoblasts inhibited myocyte differentiation and myotube formation |
| GO:0030097 hemopoiesis | IMP PMID:10021345 The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstre... | MARK AS OVER ANNOTATED | Summary: Hematopoietic defects in Nkx2-5 null yolk sac. Reason: Nkx2-5 is not a hematopoietic regulator; likely secondary to cardiac failure. Supporting Evidence: PMID:10021345 Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA cell differentiation for NK-2 TFs. Reason: Correct but very general. |
| GO:0030154 cell differentiation | IGI PMID:11390666 Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are requir... | KEEP AS NON CORE | Summary: Pharyngeal endoderm differentiation requires Nkx2.5/Nkx2.6. Reason: Correct but general. Supporting Evidence: PMID:11390666 These results demonstrated a critical role of the NK-2 homeobox genes in the differentiation, proliferation, and survival of pharyngeal endodermal cells |
| GO:0030878 thyroid gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Thyroid gland development transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Supporting Evidence: PMID:16418214 Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis |
| GO:0030878 thyroid gland development | IMP PMID:16418214 Missense mutation in the transcription factor NKX2-5: a nove... | KEEP AS NON CORE | Summary: Nkx2-5 null embryos have thyroid bud hypoplasia. Reason: Supported; extracardiac non-core. Supporting Evidence: PMID:16418214 Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis |
| GO:0030878 thyroid gland development | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Thyroid gland development transferred from human. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. Supporting Evidence: PMID:16418214 Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Protein-containing complex (generic). Reason: Uninformative; more specific complex terms exist (GO:0090575, GO:1990664). |
| GO:0032991 protein-containing complex | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Protein-containing complex (generic). Reason: Uninformative; more specific complex terms exist (GO:0090575, GO:1990664). |
| GO:0032993 protein-DNA complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Protein-DNA complex (binds DNA as homodimer/heterodimer). Reason: Correct but low information. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0032993 protein-DNA complex | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Protein-DNA complex (binds DNA as homodimer/heterodimer). Reason: Correct but low information. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0032993 protein-DNA complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Protein-DNA complex (binds DNA as homodimer/heterodimer). Reason: Correct but low information. Supporting Evidence: PMID:11042197 the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene |
| GO:0035050 embryonic heart tube development | IGI PMID:15843414 Murine T-box transcription factor Tbx20 acts as a repressor ... | KEEP AS NON CORE | Summary: Nkx2-5/Tbx20 genetic interaction in heart tube development. Reason: Abstract-only; plausible, non-core. Supporting Evidence: PMID:15843414 Loss of Tbx20 results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis |
| GO:0042802 identical protein binding | ISO GO_REF:0000096 | MODIFY | Summary: Identical protein binding (rat). Reason: Nkx2-5 homodimerizes via the homeodomain; use protein homodimerization activity. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:11042197 Csx/Nkx2.5 physically interacts with each other in vitro as well as in cells, and the HD is critical for homodimerization |
| GO:0042803 protein homodimerization activity | IDA PMID:11042197 Characterization of homo- and heterodimerization of cardiac ... | KEEP AS NON CORE | Summary: Csx/Nkx2.5 homodimerizes via its homeodomain. Reason: Directly shown; supports dimeric DNA binding. Supporting Evidence: PMID:11042197 Csx/Nkx2.5 physically interacts with each other in vitro as well as in cells, and the HD is critical for homodimerization |
| GO:0042826 histone deacetylase binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Histone deacetylase binding transferred from rat. Reason: Plausible coregulator interaction; non-core. |
| GO:0043066 negative regulation of apoptotic process | IGI PMID:11390666 Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are requir... | KEEP AS NON CORE | Summary: Enhanced apoptosis of pharyngeal endoderm in Nkx2.5;Nkx2.6 double mutants. Reason: Indirect; non-core. Supporting Evidence: PMID:11390666 we observed enhanced apoptosis and reduced proliferation in pharyngeal endodermal cells of the double-mutant embryos |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: Sequence-specific DNA binding (ortholog transfer). Reason: Correct; use the Pol II cis-regulatory sequence-specific child. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0043565 sequence-specific DNA binding | ISO GO_REF:0000096 | MODIFY | Summary: Sequence-specific DNA binding (ortholog transfer). Reason: Correct; use the Pol II cis-regulatory sequence-specific child. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0043565 sequence-specific DNA binding | ISO GO_REF:0000119 | MODIFY | Summary: Sequence-specific DNA binding (ortholog transfer). Reason: Correct; use the Pol II cis-regulatory sequence-specific child. Proposed replacements: RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| GO:0043586 tongue development | TAS PMID:9621431 Vertebrate homologs of tinman and bagpipe: roles of the home... | MARK AS OVER ANNOTATED | Summary: Tongue development, from a review noting Nkx2-5 expression. Reason: Expression in lingual muscle is not evidence of a developmental function; no loss-of-function tongue phenotype reported. Supporting Evidence: PMID:9621431 Gene targeting of Csx/Nkx2.5 showed that this gene is required for completion of the looping morphogenesis of the heart |
| GO:0045666 positive regulation of neuron differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of neuron differentiation, transferred from human. Reason: Based on forced NKX2.5 expression converting myoblasts to neuron-like cells in vitro (PMID:15653675); not a physiological role. Supporting Evidence: PMID:15653675 overexpression of NKX2.5 in C2C12 cells and primary cultures of human fetal myoblasts led to differentiation of myoblasts into neuron-like cells |
| GO:0045666 positive regulation of neuron differentiation | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Positive regulation of neuron differentiation, transferred from human. Reason: Based on forced NKX2.5 expression converting myoblasts to neuron-like cells in vitro (PMID:15653675); not a physiological role. Supporting Evidence: PMID:15653675 overexpression of NKX2.5 in C2C12 cells and primary cultures of human fetal myoblasts led to differentiation of myoblasts into neuron-like cells |
| GO:0045823 positive regulation of heart contraction | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | KEEP AS NON CORE | Summary: Perinatal Nkx2-5 loss impairs contraction (Ryr2, Nav1.5 expression). Reason: Indirect via target gene expression; non-core. Supporting Evidence: PMID:18689573 Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:11572777 A murine model of Holt-Oram syndrome defines roles of the T-... | MODIFY | Summary: Tbx5 and Nkx2-5 cooperatively transactivate Nppa and Cx40. Reason: Use Pol II-specific positive regulation. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:11572777 Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:14978031 Differential expression and function of Tbx5 and Tbx20 in ca... | MODIFY | Summary: Synergistic activation of ANF promoter by Tbx5 with other TFs (Nkx2-5). Reason: Abstract-only; use Pol II-specific term. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:14978031 Tbx5, but not Tbx20, activates a cardiac-specific promoter (atrial natriuretic factor (ANF)) alone and synergistically with other transcription factors |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: Positive regulation of DNA-templated transcription (ortholog). Reason: Use Pol II-specific child. Proposed replacements: positive regulation of transcription by RNA polymerase II |
| GO:0045893 positive regulation of DNA-templated transcription | ISO GO_REF:0000119 | MODIFY | Summary: Positive regulation of DNA-templated transcription (ortholog). Reason: Use Pol II-specific child. Proposed replacements: positive regulation of transcription by RNA polymerase II |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:16380715 Cooperative and antagonistic interactions between Sall4 and ... | ACCEPT | Summary: Nkx2-5 participates in Tbx5/Sall4 regulatory circuit in heart. Reason: Abstract-only; Nkx2-5 positive regulation of Pol II targets is core. Supporting Evidence: PMID:16380715 Tbx5 and Sall4 interact both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | ACCEPT | Summary: Nkx2-5 transcriptional activation function in cardiogenesis (YRD). Reason: Core. Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:19578358 miR-145 and miR-143 regulate smooth muscle cell fate and pla... | ACCEPT | Summary: Nkx2-5 directly activates miR-143/145. Reason: Core. Supporting Evidence: PMID:19578358 miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:8900044 Activation of the cardiac alpha-actin promoter depends upon ... | ACCEPT | Summary: Nkx-2.5 with SRF activates cardiac alpha-actin promoter. Reason: Core. Supporting Evidence: PMID:8900044 Nkx-2.5 facilitated serum response factor (SRF) DNA-binding activity to the multiple SREs found on the cardiac alpha-actin promoter and together stimulated cardiac alpha-actin promoter dependent transcription |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog transfer. Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:12392994 The basic-helix-loop-helix transcription factor HAND2 direct... | ACCEPT | Summary: HAND2/Nkx2.5 synergistic activation of ANP. Reason: Core. Supporting Evidence: PMID:12392994 HAND2 and the homeobox factor Nkx2.5 exhibit transcriptional synergy in the regulation of ANP |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:15363409 Foxh1 is essential for development of the anterior heart fie... | ACCEPT | Summary: Foxh1/Nkx2-5 activation of Mef2c enhancer. Reason: Core. Supporting Evidence: PMID:15363409 Mef2c is a direct target of Foxh1, which physically and functionally interacts with Nkx2-5 to mediate strong Smad-dependent activation of a TGFbeta response element in the Mef2c gene |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:16556915 Tbx1 affects asymmetric cardiac morphogenesis by regulating ... | ACCEPT | Summary: Tbx1 with Nkx2.5 synergistically activates the Pitx2 enhancer. Reason: Core. Supporting Evidence: PMID:16556915 Tbx1 binds to this site and activates the Pitx2 enhancer with the synergistic action of Nkx2.5 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:17604724 A molecular pathway including Id2, Tbx5, and Nkx2-5 required... | ACCEPT | Summary: Nkx2-5 and Tbx5 cooperatively regulate the Id2 promoter. Reason: Core. Supporting Evidence: PMID:17604724 A 1.2 kb fragment of the Id2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:21931855 Complex SUMO-1 regulation of cardiac transcription factor Nk... | ACCEPT | Summary: SUMO-1 enhances Nkx2-5 transcriptional activation. Reason: Core. Supporting Evidence: PMID:21931855 we confirm that SUMOylation strongly enhances Nkx2-5 transcriptional activity |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | ACCEPT | Summary: Nkx2-5 required for expression of Scn5a and Ryr2 in perinatal heart. Reason: Core activity in postnatal myocardium. Supporting Evidence: PMID:18689573 Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000008 | ACCEPT | Summary: MGI orthology transfer. Reason: Core. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISO GO_REF:0000119 | ACCEPT | Summary: Human-to-mouse transfer. Reason: Core. |
| GO:0048536 spleen development | IEA GO_REF:0000120 | ACCEPT | Summary: Spleen development (electronic). Reason: Supported by mouse genetics and human asplenia (PMID:22560297). Supporting Evidence: PMID:22560297 This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development |
| GO:0048536 spleen development | IGI PMID:22560297 Congenital asplenia in mice and humans with mutations in a P... | ACCEPT | Summary: Pbx1/Nkx2-5 genetic interaction in spleen mesenchyme. Reason: Pbx/Nkx2-5/p15 module essential for spleen development. Supporting Evidence: PMID:22560297 the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors PMID:22560297 This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development |
| GO:0048536 spleen development | IGI PMID:22560297 Congenital asplenia in mice and humans with mutations in a P... | ACCEPT | Summary: Pbx/Nkx2-5/p15 module in spleen development (second genetic interactor). Reason: Core extracardiac role. Supporting Evidence: PMID:22560297 This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development |
| GO:0048536 spleen development | ISO GO_REF:0000119 | ACCEPT | Summary: Human-to-mouse transfer of spleen development. Reason: Human NKX2-5 P236H causes isolated congenital asplenia. Supporting Evidence: PMID:22560297 This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development |
| GO:0048536 spleen development | TAS PMID:9621431 Vertebrate homologs of tinman and bagpipe: roles of the home... | ACCEPT | Summary: Review statement on Nkx2-5 roles (spleen). Reason: TAS from an early review; spleen role is now established genetically by PMID:22560297. |
| GO:0048738 cardiac muscle tissue development | IMP PMID:7628699 Myogenic and morphogenetic defects in the heart tubes of mur... | ACCEPT | Summary: Nkx2-5 null hearts lack ventricular Mlc2v expression; myogenesis defects. Reason: Core cardiac muscle development role. Supporting Evidence: PMID:7628699 the myosin light-chain 2V gene (MLC2V) was not expressed in mutant hearts PMID:7628699 The data demonstrate that Nkx2-5 is essential for normal heart morphogenesis, myogenesis, and function |
| GO:0051891 positive regulation of cardioblast differentiation | IMP PMID:11889119 Csx/Nkx2-5 is required for homeostasis and survival of cardi... | UNDECIDED | Summary: Positive regulation of cardioblast differentiation attributed to an adult-heart study. Reason: The cached abstract concerns adult cardiomyocyte survival, not cardioblast differentiation; full text unavailable, so cannot verify. Supporting Evidence: PMID:11889119 These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype |
| GO:0055005 ventricular cardiac myofibril assembly | IMP PMID:19546853 Slow progressive conduction and contraction defects in loss ... | KEEP AS NON CORE | Summary: Postnatal Nkx2-5 loss leads to contraction defects (myofibril assembly). Reason: Plausible indirect; non-core. Supporting Evidence: PMID:19546853 Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age |
| GO:0055007 cardiac muscle cell differentiation | IDA PMID:9857019 Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other... | ACCEPT | Summary: Nkx2-5 overexpression initiates cardiomyogenesis in P19 cells. Reason: Core. Supporting Evidence: PMID:9857019 Nkx2-5 expression induced cardiomyogenesis in these cultures aggregated without Me2SO |
| GO:0055007 cardiac muscle cell differentiation | IGI PMID:19035347 Cooperative interaction of Nkx2.5 and Mef2c transcription fa... | ACCEPT | Summary: Nkx2.5;Mef2c double mutants have defective ventricular cardiomyocyte differentiation. Reason: Core. Supporting Evidence: PMID:19035347 ventricular hypoplasia is the result of defective ventricular cell differentiation |
| GO:0055007 cardiac muscle cell differentiation | IMP PMID:10021345 The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstre... | ACCEPT | Summary: ES chimaera analysis: Nkx2.5 required for later cardiomyocyte differentiation. Reason: Core. Supporting Evidence: PMID:10021345 Csx/Nkx2.5 is required for later differentiation of cardiac myocytes |
| GO:0055007 cardiac muscle cell differentiation | IMP PMID:17234970 Molecular pathway for the localized formation of the sinoatr... | ACCEPT | Summary: Nkx2-5 drives working (atrial) myocardium differentiation versus SAN. Reason: Core. Supporting Evidence: PMID:17234970 Nkx2-5 is essential for establishing a gene expression border between the atrium and sinoatrial node |
| GO:0055008 cardiac muscle tissue morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cardiac muscle tissue morphogenesis (ortholog). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0055008 cardiac muscle tissue morphogenesis | IMP PMID:21640717 Ectopic expression of Nkx2.5 suppresses the formation of the... | KEEP AS NON CORE | Summary: Ectopic Nkx2.5 converts SAN to working myocardium. Reason: Gain-of-function; non-core. Supporting Evidence: PMID:21640717 tissue specific overexpression of Nkx2.5 in the heart leads to severe hypoplasia of the SAN and the venous valves |
| GO:0055008 cardiac muscle tissue morphogenesis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Cardiac muscle tissue morphogenesis (ortholog). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0055013 cardiac muscle cell development | IMP PMID:19166829 Shox2 is essential for the differentiation of cardiac pacema... | KEEP AS NON CORE | Summary: Shox2 represses Nkx2-5 to permit pacemaker cell differentiation. Reason: Supported; non-core. Supporting Evidence: PMID:19166829 Shox2 plays an essential role in the SAN and pacemaker development by controlling a genetic cascade through the repression of Nkx2-5 |
| GO:0055013 cardiac muscle cell development | IMP PMID:21640717 Ectopic expression of Nkx2.5 suppresses the formation of the... | KEEP AS NON CORE | Summary: Nkx2.5 overexpression perturbs SAN cardiomyocyte development. Reason: Supported; non-core. Supporting Evidence: PMID:21640717 tissue specific overexpression of Nkx2.5 in the heart leads to severe hypoplasia of the SAN and the venous valves |
| GO:0055014 atrial cardiac muscle cell development | TAS PMID:9621431 Vertebrate homologs of tinman and bagpipe: roles of the home... | KEEP AS NON CORE | Summary: Review: atrial cardiac muscle cell development. Reason: Plausible; non-core. Supporting Evidence: PMID:9621431 Gene targeting of Csx/Nkx2.5 showed that this gene is required for completion of the looping morphogenesis of the heart |
| GO:0055015 ventricular cardiac muscle cell development | TAS PMID:9621431 Vertebrate homologs of tinman and bagpipe: roles of the home... | KEEP AS NON CORE | Summary: Review: ventricular cardiac muscle cell development (Mlc2v). Reason: Supported by PMID:7628699; non-core. Supporting Evidence: PMID:9621431 Gene targeting of Csx/Nkx2.5 showed that this gene is required for completion of the looping morphogenesis of the heart |
| GO:0055117 regulation of cardiac muscle contraction | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | KEEP AS NON CORE | Summary: Perinatal Nkx2-5 loss impairs contraction. Reason: Indirect through target genes; non-core. Supporting Evidence: PMID:18689573 Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction |
| GO:0060037 pharyngeal system development | IGI PMID:11390666 Nkx2.5 and Nkx2.6, homologs of Drosophila tinman, are requir... | KEEP AS NON CORE | Summary: Nkx2.5;Nkx2.6 required for pharynx. Reason: Supported; non-core. Supporting Evidence: PMID:11390666 These results demonstrated a critical role of the NK-2 homeobox genes in the differentiation, proliferation, and survival of pharyngeal endodermal cells |
| GO:0060038 cardiac muscle cell proliferation | IGI PMID:17350578 An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart p... | KEEP AS NON CORE | Summary: Nkx2-5/Bmp2/Smad1 feedback controls SHF progenitor proliferation. Reason: Supported; non-core. Supporting Evidence: PMID:17350578 feedback repression of Bmp2/Smad1 signaling by Nkx2-5 critically regulates SHF proliferation and outflow tract (OFT) morphology PMID:17350578 Smad1 deletion in Nkx2-5 mutants rescued SHF proliferation and OFT development |
| GO:0060043 regulation of cardiac muscle cell proliferation | IDA PMID:20713518 Foxp1 coordinates cardiomyocyte proliferation through both c... | KEEP AS NON CORE | Summary: Transgenic Nkx2.5 overexpression increases cardiomyocyte proliferation. Reason: Supported; non-core. Supporting Evidence: PMID:20713518 transgenic overexpression of Nkx2.5 leads to increased cardiomyocyte proliferation and increased ventricular mass |
| GO:0060047 heart contraction | IGI PMID:21690310 Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regula... | KEEP AS NON CORE | Summary: Nkx2-5;Cdc42 compound heterozygotes have cardiac output defects. Reason: Indirect; non-core. Supporting Evidence: PMID:21690310 we examined compound heterozygous mutant mice and found conduction system and cardiac output defects |
| GO:0060048 cardiac muscle contraction | IMP PMID:19546853 Slow progressive conduction and contraction defects in loss ... | KEEP AS NON CORE | Summary: Postnatal Nkx2-5 loss causes contraction defects. Reason: Indirect; non-core. Supporting Evidence: PMID:19546853 Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age |
| GO:0060261 positive regulation of transcription initiation by RNA polymerase II | IDA PMID:8887666 Recruitment of the tinman homolog Nkx-2.5 by serum response ... | MODIFY | Summary: SRF recruits Nkx-2.5 to activate cardiac alpha-actin transcription. Reason: Evidence shows transcriptional activation, not specifically the initiation step. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:8887666 SRF recruited Nkx-2.5 to the alpha-actin promoter |
| GO:0060347 heart trabecula formation | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | KEEP AS NON CORE | Summary: Nkx2-5 mutants affect trabeculation. Reason: Supported; non-core. Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0060411 cardiac septum morphogenesis | IMP PMID:16510504 A tyrosine-rich domain within homeodomain transcription fact... | KEEP AS NON CORE | Summary: YRD-mutant chimaeras have septal malformations. Reason: Supported; non-core. Supporting Evidence: PMID:16510504 the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo |
| GO:0060412 ventricular septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Septum morphogenesis transferred from human (septal defects in NKX2-5 patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0060412 ventricular septum morphogenesis | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Septum morphogenesis transferred from human (septal defects in NKX2-5 patients). Reason: Electronic/orthology transfer from human NKX2-5 (or rat Nkx2-5); the mouse protein is a 1:1 ortholog. |
| GO:0060413 atrial septum morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: Septum morphogenesis transferred from human (septal defects in NKX2-5 patients). Reason: Revised from KEEP_AS_NON_CORE for consistency with the human NKX2-5 review (ortholog audit 2026-10-12), where atrial septal defect is the hallmark NKX2-5 phenotype and atrial septum morphogenesis is a core process. Orthology transfer from human NKX2-5 to the 1:1 mouse ortholog is sound; Nkx2-5 heterozygous mice also show atrial septal defects. Supporting Evidence: PMID:9651244 These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis |
| GO:0060413 atrial septum morphogenesis | ISO GO_REF:0000119 | ACCEPT | Summary: Septum morphogenesis transferred from human (septal defects in NKX2-5 patients). Reason: Revised from KEEP_AS_NON_CORE for consistency with the human NKX2-5 review (ortholog audit 2026-10-12), where atrial septal defect is the hallmark NKX2-5 phenotype and atrial septum morphogenesis is a core process. Orthology transfer from human NKX2-5 to the 1:1 mouse ortholog is sound; Nkx2-5 heterozygous mice also show atrial septal defects. Supporting Evidence: PMID:9651244 These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis |
| GO:0060928 atrioventricular node cell development | IMP PMID:19546853 Slow progressive conduction and contraction defects in loss ... | KEEP AS NON CORE | Summary: Postnatal Nkx2-5 loss causes AV block. Reason: Supported; non-core. Supporting Evidence: PMID:19546853 Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age |
| GO:0060929 atrioventricular node cell fate commitment | IMP PMID:15109497 Nkx2-5 pathways and congenital heart disease; loss of ventri... | KEEP AS NON CORE | Summary: Ventricular Nkx2-5 KO: hypoplastic AV node and loss of conduction lineage specification. Reason: Supported; non-core. Supporting Evidence: PMID:15109497 At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells PMID:15109497 loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes |
| GO:0060971 embryonic heart tube left/right pattern formation | IMP PMID:9192865 Homeodomain factor Nkx2-5 controls left/right asymmetric exp... | KEEP AS NON CORE | Summary: Nkx2-5 controls left-sided eHand expression in heart tube. Reason: Supported; non-core. Supporting Evidence: PMID:9192865 In hearts of embryos lacking the homeobox gene Nkx2-5, which do not loop, left-sided eHand expression was abolished |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Binding to partner DNA-binding TFs (GATA4, TBX5, SRF, MEF2C, HAND2, TBX20). Reason: Well supported in mouse (PMID:9584153, PMID:19035347). Supporting Evidence: PMID:9584153 Coimmunoprecipitation experiments demonstrate that Csx and GATA4 associate intracellularly PMID:19035347 Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISO GO_REF:0000119 | ACCEPT | Summary: Binding to partner DNA-binding TFs (GATA4, TBX5, SRF, MEF2C, HAND2, TBX20). Reason: Well supported in mouse (PMID:9584153, PMID:19035347). Supporting Evidence: PMID:9584153 Coimmunoprecipitation experiments demonstrate that Csx and GATA4 associate intracellularly PMID:19035347 Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IDA PMID:19479054 NKX2-5 regulates the expression of beta-catenin and GATA4 in... | MARK AS OVER ANNOTATED | Summary: NKX2-5 represses beta-catenin (CTNNB1) gene expression via promoter NKEs. Reason: Transcriptional repression of CTNNB1 is not demonstrated to regulate canonical Wnt signaling output; better captured by negative regulation of Pol II transcription. Supporting Evidence: PMID:19479054 NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5 |
| GO:0090575 RNA polymerase II transcription regulator complex | IEA GO_REF:0000107 | ACCEPT | Summary: RNA polymerase II transcription regulator complex (e.g. with Tbx2, Tbx5, GATA4). Reason: Supported by PMID:12023302. Supporting Evidence: PMID:12023302 Tbx2 formed a complex with Nkx2.5 on the ANF TBE-NKE, and was able to repress ANF promoter activity |
| GO:0090575 RNA polymerase II transcription regulator complex | ISO GO_REF:0000119 | ACCEPT | Summary: RNA polymerase II transcription regulator complex (e.g. with Tbx2, Tbx5, GATA4). Reason: Supported by PMID:12023302. Supporting Evidence: PMID:12023302 Tbx2 formed a complex with Nkx2.5 on the ANF TBE-NKE, and was able to repress ANF promoter activity |
| GO:1903779 regulation of cardiac conduction | IMP PMID:18689573 Perinatal loss of Nkx2-5 results in rapid conduction and con... | KEEP AS NON CORE | Summary: Perinatal Nkx2-5 loss causes conduction defects. Reason: Indirect via Scn5a etc.; non-core. Supporting Evidence: PMID:18689573 Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit |
| GO:1990664 Nkx-2.5 complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nkx-2.5 complex (homodimer). Reason: Homodimerization shown (PMID:11042197); non-core. Supporting Evidence: PMID:11042197 Csx/Nkx2.5 physically interacts with each other in vitro as well as in cells, and the HD is critical for homodimerization |
| GO:1990664 Nkx-2.5 complex | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Nkx-2.5 complex (homodimer). Reason: Homodimerization shown (PMID:11042197); non-core. Supporting Evidence: PMID:11042197 Csx/Nkx2.5 physically interacts with each other in vitro as well as in cells, and the HD is critical for homodimerization |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Sequence-specific double-stranded DNA binding (ortholog). Reason: Correct for homeodomain. |
| GO:1990837 sequence-specific double-stranded DNA binding | ISO GO_REF:0000119 | ACCEPT | Summary: Sequence-specific double-stranded DNA binding (ortholog). Reason: Correct for homeodomain. |
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Download this section (compressed HTML)Q: Which Nkx2-5 target genes are directly repressed versus activated in vivo, and does repression require specific corepressors (HIPK, Groucho/TLE, Jarid2) or partner TFs such as Tbx2/Tbx3?
Q: Is the Nkx2-5 requirement in the postnatal conduction system (Scn5a, Ryr2, Cx40 regulation) mechanistically distinct from its embryonic role in conduction lineage specification?
Q: Should 'adult heart development' annotations based on embryonic-lethal null phenotypes be revised to 'heart development'?
Experiment: CUT&RUN/ChIP-seq for endogenous Nkx2-5 in SHF progenitors, ventricular myocardium and conduction cells, combined with acute degron depletion and nascent transcription (PRO-seq) to separate direct activation from repression targets.
Hypothesis: Nkx2-5 directly represses Bmp2/Isl1/Hcn4 and activates Nppa/Scn5a/Id2 through distinct enhancer classes and partner TFs.
Type: genome-wide binding with acute depletion
Experiment: Conditional Nkx2-5 deletion in Tlx1-lineage splenic mesenchyme (bypassing cardiac lethality) with lineage tracing and p15Ink4b compound deletion.
Hypothesis: Nkx2-5 is cell-autonomously required in splenic mesenchymal progenitors for proliferation via p15Ink4b repression.
Type: conditional mouse genetics
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