Core ligand identity: Edn1 encodes preproendothelin-1, processed to endothelin-1, a secreted vasoactive peptide ligand for endothelin receptors EDNRA and EDNRB. UniProt summarizes endothelins as "endothelium-derived vasoconstrictor peptides" and describes ET-1 as a "Probable ligand for G-protein coupled receptors EDNRA and EDNRB." [file:mouse/Edn1/Edn1-uniprot.txt]
Core receptor binding and signaling: Endothelin stimulates high-affinity receptor binding and phospholipase C signaling in fibroblasts; the abstract reports that endothelin "specifically binds to a single class of high affinity receptors" and "stimulates phospholipase C with the production of second messengers inositol trisphosphate and 1,2-diacylglycerol." [PMID:2542249 "A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts.", "specifically binds to a single class of high affinity receptors ... stimulates phospholipase C"]
Vascular and blood-pressure physiology: Edn1-null mice "die of respiratory failure at birth and have morphological abnormalities of the pharyngeal-arch-derived craniofacial tissues and organs"; heterozygotes "develop elevated blood pressure." This supports Edn1 as a physiological regulator of vascular tone and blood pressure, while broad organismal phenotypes remain non-core relative to ligand activity. [PMID:8152482 "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1.", "ET-1+/- heterozygous mice, which produce lower levels of ET-1 than wild-type mice, develop elevated blood pressure"]
Cardiovascular development: Edn1-/- mice have "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract." These defects support developmental annotations for heart and great-vessel morphogenesis, but they are best treated as non-core developmental consequences of endothelin receptor signaling. [PMID:7615798 "Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.", "cardiovascular malformations including interrupted aortic arch ... and ventricular septal defect with abnormalities of the outflow tract"]
Neural crest patterning: Edn1/Ednra signaling is required for branchial arch patterning; one paper states that Edn1 "regulates the dorsoventral branchial arch patterning in mice." These annotations are supported when specific to cranial/cardiac neural crest patterning but should not be generalized to all development. PMID:15110048
Sympathetic axon guidance: Venous endothelin-1 is a direct guidance cue; Manousiouthakis et al. report that "vascular-derived endothelin controls growth and guidance of the STG axons to the heart." Poltavski et al. report that "endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart." These support cardiac sympathetic axon-guidance annotations as well-supported but non-core developmental signaling roles. [PMID:24875861 "Venous endothelin guides sympathetic innervation of the developing mouse heart.", "vascular-derived endothelin controls growth and guidance of the STG axons to the heart"] [PMID:30735130 "Venous endothelin modulates responsiveness of cardiac sympathetic axons to arterial semaphorin.", "endothelin-1 induces sympathetic neurons expressing the receptor Ednra to project to the vena cavae leading to the heart"]
Kidney and podocyte disease evidence: Endothelin-1 stimulation of primary mouse podocytes "elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs)" and Ednra-mediated glomerular crosstalk is reported in diabetic kidney models. These support renal/podocyte annotations when direct, but disease-model terms are not core Edn1 function. [PMID:24722437 "Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.", "elicited rapid calcium transients mediated by endothelin type A receptors"] PMID:31402170
Curation judgment: broad signaling outputs such as MAPK, ERK, JNK, PKA, calcium homeostasis, transcription, proliferation, toxic-substance response, hypoxia response, and many hormone-response terms are downstream or context-specific readouts of endothelin receptor activation. Prefer the more specific ligand/receptor-binding and endothelin receptor signaling terms; keep direct mouse developmental or renal phenotypes as non-core rather than core functions.
Falcon integration: the Falcon report independently supports the same core model: Edn1 encodes the preproendothelin-1 precursor processed to mature ET-1, a secreted peptide hormone/vasoconstrictor that signals through ETA/EDNRA and ETB/EDNRB receptors. It also emphasizes extracellular ligand localization, endothelial/glomerular production, vascular tone, renal physiology, and pharyngeal-arch morphogen activity; this reinforced ACCEPT for hormone/endothelin receptor binding and endothelin receptor signaling terms, while keeping broad downstream or phenotype terms non-core or over-annotated. [file:mouse/Edn1/Edn1-deep-research-falcon.md "encodes a secreted peptide hormone precursor"; "signals primarily via two class A GPCRs"]