PENDING.The SLIT-seeded PTN002911625 trace does not establish a NOTCH1-specific axon-guidance mechanism, but it also does not refute one. The axon-guidance IBA is now UNDECIDED: direct Drosophila evidence identifies a noncanonical Notch/Disabled/Trio pathway for axon growth and guidance independent of canonical cell-fate signaling [PMID:18062953, “Molecular separation of two signaling pathways for the receptor, Notch.”]. A neutral focused OpenScientist report has been submitted by the coordinating reviewer to distinguish directional guidance, neurite growth and cell-fate effects in human NOTCH1; no duplicate was launched. Enzyme-inhibitor activity is retained as non-core because Notch ankyrin repeats compete with HIF for FIH hydroxylation [PMID:17573339, “Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor.”], with follow-up FIH sequestration/cross-talk evidence PMID:18299578. Broad transcription/coactivator and cell-periphery terms remain core where they directly capture canonical NOTCH1 function. DLL3 was removed from the list of canonical activating trans ligands. All 378 rows were screened, preserving pleiotropic developmental processes as non-core where appropriate.
The completed OpenScientist report is incorporated with a material identifier correction. The report calls the fly/mouse WITH/FROM genes Notch orthologs, but FlyBase FBgn0264089 is sli, and MGI:1315202/1315203/1315205 are Slit3, Slit1 and Slit2. A fresh QuickGO exact-term query confirms those identifiers. Independent primary Notch evidence remains biologically relevant: PMID:21246649 establishes the Trio GEF1/Rac contribution, and PMID:29343637 separates cleavage/tyrosine-dependent axon patterning from cell-fate signaling. PMID:10465425 measures neurite outgrowth/morphology, while PMID:27040987 examines mammalian noncanonical synaptic-protein expression. Neither these different outputs nor absent STRING edges prove loss of guidance. The report did not align the fly determinants or reconstruct the PAINT tree; human conservation remains UNDECIDED. The report is complete and no duplicate query was launched.
Automated deep research was not run for this section. Sources were found with PubMed
searches, PMIDs and titles checked against PubMed, fetched with just fetch-pmid, and read
in the cache. All four papers below have full_text_available: true.
| Core function (existing review) | Classification | Basis |
|---|---|---|
| Transmembrane signaling receptor for DSL ligands; Notch signaling pathway; cell differentiation | Animal-specific (with an unresolved choanozoan prelude) | No receptor with metazoan-level sequence similarity in M. brevicollis or Capsaspora; DSL ligands animal-specific in 2009. One Mylnosiga protein with canonical EGF-LNR-TM-ANK order and a Delta-like protein in one choanoflagellate (PMID:29848444), identified by architecture only, untested biochemically. Cell differentiation and juxtacrine signaling between cells of one body is a multicellular process. |
| NICD as transcription coactivator in the CSL-NICD-MAML ternary complex | Animal-specific as an activity of Notch; partner ancestral | CSL is present in Capsaspora and is opisthokont-old (PMID:23942320, PMID:19825158), so the DNA-binding partner is premetazoan. The coactivator activity requires a NICD (RAM + ANK) that no unicellular protein has been shown to have, and MAML is eumetazoan-only and absent from sponges. The MAML1-RBPJ-ICN1 complex term is therefore animal-specific (and arguably eumetazoan). |
| Calcium ion binding by EGF (and LNR) repeats | Ancestral at the domain level, not at the protein level | Ca-binding EGF and LNR modules are older than animals (PMID:19825158), but this says nothing about a NOTCH1 ortholog; the activity is a property of the domain type wherever it occurs. |
Answer to the project question: NOTCH1 holds up as an animal-innovation comparator, with
one caveat. None of its core functions has a demonstrated premetazoan counterpart as a
protein activity. What predates animals is (a) its downstream DNA-binding partner CSL/RBPJ
(opisthokont-old, present in Capsaspora), and (b) its constituent domains. The one
challenge to "animal-specific" is the Mylnosiga fluctuans protein with full Notch domain
order (PMID:29848444), which its authors say may reflect a Choanozoa-level origin followed
by loss, or convergent domain shuffling. Nothing is known of its function. The control
therefore holds for function, but it is not a clean "absent in all unicellular relatives"
control for gene presence.
NOTCH1 IBA rows come from two PANTHER nodes in PTHR45836:
- PTN001933897 (taxon:6072 Eumetazoa in interpro/panther/PTHR45836/PTHR45836-paint.tsv):
Notch signaling pathway, plasma membrane, cell surface, receptor complex.
- PTN002911625: axon guidance (SLIT-seeded; see the 2026-09-20 note above).
QuickGO withFrom=PANTHER:<PTN>&taxonUsage=descendants returned 0 annotations for both
nodes in Choanoflagellata (28009), Filasterea (2687318) and Ichthyosporea (127916).
Controls: PTN001933897 has 3943 annotations, all within Metazoa (33208 count = Eukaryota
2759 count); PTN002911625 has 125, also all within Metazoa. No animal tissue, organ or
development term from these nodes reaches a unicellular holozoan. This is the expected
negative result for an animal-innovation comparator, and it is consistent with the Notch
node being placed at Eumetazoa. Note that the choanoflagellate Notch-like proteins
(e.g. from Mylnosiga) are from transcriptomes not in UniProt reference proteomes, so their
absence from QuickGO is not by itself evidence against homology.
No existing review action changed: the evolutionary evidence does not bear on any IBA row
(all propagation stays within animals). Added an evolutionary-origin sentence to the
description, the four papers to references, and suggested questions.