Nkx2-5 (mouse, P42582, NKX25_MOUSE) — curation notes

Provenance note

Automated deep research could not be run for this gene (falcon provider returned
HTTP 402, OpenAI provider returned HTTP 401). No -deep-research-<provider>.md
file exists. These notes were assembled manually from the cached publications in
publications/ (most are abstract-only; full text available for PMIDs 11390666,
17350578, 18689573, 18722343, 19035347, 19166829, 19479054, 19546853, 19578358,
21379568, 21640717, 21931855, 22192413, 22560297, 23028370) and the UniProt record
Nkx2-5-uniprot.txt.

Identity and domain architecture

• NK-2 class homeodomain transcription factor (also called Csx / Csx1), vertebrate
  ortholog of Drosophila tinman; belongs to PANTHER PTHR24340:SF28 (HOMEOBOX PROTEIN
  NKX-2.5) per UniProt cross-reference.
• Homeodomain binds NK2 elements (NKEs; e.g. TNAAGTG/TCCACTTTCC-type sites) in target
  promoters/enhancers; additional conserved motifs include the TN domain, the NK2-specific
  domain and a tyrosine-rich domain (YRD) required in vivo
  PMID:16510504.
• Binds DNA as monomer and homodimer
  PMID:11042197.
• Nuclear; SUMOylation enhances activity
  PMID:21931855.

Molecular function: cardiac transcription factor, activator and repressor

• Activator of cardiac structural/regulatory genes (Nppa/ANF, cardiac alpha-actin,
  Cx40, myocardin, Mef2c, Id2, miR-143/145), usually in combination with partner TFs:
• GATA4 PMID:9584153
• SRF PMID:8887666
• TBX5 PMID:11572777
• TBX20 PMID:14550786
• MEF2C PMID:19035347
• HAND2 PMID:12392994
• FOXH1 PMID:15363409
• Direct targets: myocardin PMID:14645532; miR-143/145 PMID:19578358; Id2 PMID:17604724.
• Repressor functions (context-dependent): with TBX2 represses Nppa in the AV canal
  PMID:12023302;
  represses the pacemaker program (Hcn4, Tbx3) at the atrium/SAN border
  PMID:17234970;
  feedback repression of Bmp2/Smad1 in the second heart field
  PMID:17350578.
• Coregulators: HIPK corepressors PMID:9748262;
  JARID2/JMJ PMID:15542826;
  CAMTA2 coactivator PMID:16678093;
  WHSC1/NSD2 H3K36 methyltransferase PMID:19483677;
  UTX/UTY PMID:22192413.
• Genome-wide binding in cardiomyocytes PMID:21379568.

Biological roles (mouse genetics)

• Null embryos: heart tube forms but looping is not initiated, death ~E9-10, loss of
  Mlc2v (ventricular differentiation marker)
  PMID:7628699
  PMID:7628699;
  commitment to cardiac lineage itself is not lost
  PMID:7628699.
• Required for later cardiomyocyte differentiation (ES chimeras)
  PMID:10021345.
• Yolk sac vascular and hematopoietic defects in nulls
  PMID:10021345
  — most likely secondary to cardiac failure (Nkx2-5 is not a yolk sac vascular/blood regulator).
• Ventricle formation with Hand2 and Mef2c (double mutants lack ventricle)
  PMID:11784028
  PMID:19035347.
• Second heart field: Nkx2-5/Bmp2/Smad1 negative feedback
  PMID:17350578.
• Left/right asymmetric eHand expression
  PMID:9192865.
• Conduction system: dosage-dependent; AV node primordium absent in nulls; Purkinje
  fibre formation requires Nkx2-5 cell-autonomously; Tbx5/Nkx2-5/Id2 pathway
  PMID:15085192
  PMID:17250822
  PMID:17604724.
• Ventricular-restricted KO: AV block, trabecular overgrowth (Bmp10)
  PMID:15109497.
• Perinatal/postnatal requirement: Scn5a (Nav1.5), Ryr2 expression, conduction and
  contraction PMID:18689573
  PMID:19546853.
• Adult cardiomyocyte survival PMID:11889119.
• SAN: Nkx2-5 must be excluded from SAN (Shox2 represses it)
  PMID:21640717.
• Pulmonary myocardium identity PMID:17823370.
• Proepicardium PMID:18722343.
• Cardiomyocyte proliferation PMID:20713518.

Extracardiac roles

• Spleen (Pbx1/Nkx2-5/p15 module; Nkx2-5 marks splenic mesenchymal progenitors; Tlx1
  is a parallel spleen regulator)
  PMID:22560297.
• Pharynx (redundant with Nkx2-6)
  PMID:11390666.
• Thyroid bud PMID:16418214.
• Overexpression in C2C12 myoblasts inhibits myotube formation and induces neuron-like
  cells PMID:15653675
  — artificial gain-of-function, not a physiological role.

Curation decisions summary

• Core: sequence-specific RNA pol II TF activity (GO:0000981 / GO:0000978), positive and
  negative regulation of Pol II transcription, nucleus; heart development (looping,
  ventricle formation, cardiomyocyte differentiation, conduction system) and spleen development.
• Generic terms (DNA binding, sequence-specific DNA binding, chromatin binding,
  GO:0003700, GO:0001216, positive regulation of DNA-templated transcription) modified to
  the Pol II-specific children.
• protein binding IPI rows modified to TF binding (GO:0061629) or coregulator binding
  (GO:0001221/GO:0001222/GO:0001223) depending on the partner.
• Marked as over-annotated: vasculogenesis, hemopoiesis (yolk sac secondary to heart
  failure), apoptotic process involved in heart morphogenesis, tongue development (expression
  only), skeletal myotube/neuron differentiation (C2C12 overexpression), positive regulation of
  sodium ion transport and negative regulation of canonical Wnt signaling (indirect expression
  effects), cytosol, protein-containing complex, tissue development.
• No GO-CAM model in gocams/index.tsv includes Nkx2-5 (P42582).

2026-10-12 Ortholog/family audit (human NKX2-5, DROME tin)

• GOA refresh (just fetch-gene mouse Nkx2-5): 214 rows fetched; review already covered all 206 distinct (term, evidence, reference) keys; no new or stale rows.
• PANTHER: mouse and human PTHR24340:SF28 (NKX-2.5); fly tin PTHR24340:SF41. Core MF agrees across all three (GO:0000981 and GO:0000978 accepted; GO:0061629 partner-TF binding core in mouse and human).
• Contradictions resolved:
• GO:0003162 atrioventricular node development: mouse IMP KEEP_AS_NON_CORE vs human ACCEPT (in a human core function). Changed mouse to ACCEPT and added to the conduction-system core function PMID:15085192.
• GO:0060413 atrial septum morphogenesis: mouse IEA/ISO KEEP_AS_NON_CORE vs human IMP ACCEPT (core). Changed mouse rows to ACCEPT and added to the same core function PMID:9651244.
• GO:0048536 spleen development: mouse ACCEPT (with a core function) vs human KEEP_AS_NON_CORE. Changed human IMP/ISS rows to ACCEPT and added a matching spleen core function to human [PMID:22560297 "This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development"; the same paper reports the human P236H asplenia allele].
• GO:0030154 cell differentiation (shared IBA, PTN000678271): mouse KEEP_AS_NON_CORE vs human ACCEPT. Changed human IBA and ISS rows to KEEP_AS_NON_CORE (too general; the specific core process is cardiac muscle cell differentiation).
• Stylistic differences left as-is: the mouse review MODIFYs parent MF terms (GO:0003700 -> GO:0000981; GO:0043565, GO:0000976, GO:0003677, GO:0003682 -> GO:0000978) where human ACCEPTs them. Both reviews treat the same function as core, so there is no disagreement about the biology. Finer heart-development BPs (septum secundum, ventricular septum, cardiac muscle cell development, embryonic heart tube development) are ACCEPT in human and KEEP_AS_NON_CORE in mouse; this granularity choice was not harmonised.
• Fly tin accepts the cell differentiation IBA; flagged, not edited.