- 1 PTHR12027 (Wnt family) tree annotation discussion
- 2 Questions for MOD curators
- 3 Questions for ontology curators
PTHR12027 (Wnt family) tree annotation discussion
This is a list of questions that arose while PAINTing the Wnt family. Please comment liberally, and please sign your comments. -Mike
Questions for MOD curators
- Question:GO:0004871 "signal transducer activity" has the comment "Ligands do NOT have the molecular function 'signal transducer activity'." Can you please clarify the 4871 IGI on wnt-2?
- Curator answer: I removed the manual IGI annotation to signal transducer activity, but also noticed that we have the same annotation in WB as an IEA via the InterPro2GO mapping. This annotation also gets applied to the other C. elegans Wnts via the same mapping.
- InterPro:IPR005816 Secreted growth factor Wnt protein > GO:signal transducer activity ; GO:0004871
- There are some others in the InterPro2GO mappings file that should also be checked:
- InterPro:IPR005817 Wnt superfamily > GO:signal transducer activity ; GO:0004871
- InterPro:IPR009139 Wnt-1 protein > GO:signal transducer activity ; GO:0004871 (and many other Wnt-number proteins share this mapping)
- I'll submit this as a SourceForge item.
- Question: Please verify the Wnt9a GO:0043028 "caspase regulator activity" annotation. Is this an actual molecular function of Wnt9a or just a downstream effect?
- Curator answer:
- Yes, I made two annotations:
- caspase regulator activity;
- negative regulation of caspase activity
- based on authors' statements, results' section "Reduction of caspase-3 activity by Wnt14", Fig. 3.
- (Question continued) Is this an actual molecular function of Wnt9a or just a downstream effect?
- Author use transfection experiments to assay effect "of Wnt14 on caspase-3 activity". In order to correspond to authors' statements, both annotations seem appropriate to me (Authors use term activity, not activation. I wanted to be close to authors' statements.) Whether it is a direct or indirect effect - I can not conclude from the presented data. Author discuss how exactly Wnt14 may be involved in caspase-3 regulation.
- Question follow-up (from Mike): Is this the MF GO:0043028 "caspase regulator activity" or the BP GO:0043281 "regulation of caspase activity"? If Wnt isn't actually touching caspase-3 -- and I think they're in separate compartments so they can't -- then it can't be the MF. The downstream effect would have to be the BP, right?
- All: There are multiple annotations to "plasma membrane." Do you agree that this is valid for a ligand?
- Mike's comments:
- My main question is about the general permissibility of the term GO:0005886 "plasma membrane" for this purpose. It is defined as "The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins." I think "associated" doesn't just mean "touching the bilayer" but also includes anything daisy-chained to it, in this case a ligand bound to a receptor which is integral to the membrane. Based on this understanding, I propagated "plasma membrane" to all the Wnts. If the consensus is that this is not the proper meaning, then I'll remove that inference.
- Here are the 3 examples (from 2 proteins) in the Wnt family:
- Rat Wnt7b, from PMID 18177422. I can't access the fulltext, so I can't assess it.
- Zebrafish wnt11, from PMID 17130287: "We show that in zebrafish embryonic cells, Wnt11 locally functions at the plasma membrane by accumulating its receptor, Frizzled 7, on adjacent sites of cell contacts. Wnt11-induced Frizzled 7 accumulations recruit the intracellular Wnt signaling mediator Dishevelled, as well as Wnt11 itself, and locally increase cell contact persistence. This increase in cell contact persistence is mediated by the local interaction of Wnt11, Frizzled 7, and the atypical cadherin Flamingo at the plasma membrane, and it does not require the activity of further downstream effectors of Wnt11 signaling, such as RhoA and Rok2. We propose that Wnt11, by interacting with Frizzled 7 and Flamingo, modulates local cell contact persistence to coordinate cell movements during gastrulation."
- Zebrafish wnt11, from PMID 16198297: "Here, we show that Wnt11 functions during zebrafish gastrulation by regulating the cohesion of mesodermal and endodermal (mesendodermal) progenitor cells. Importantly, we demonstrate that Wnt11 activity in this process is mediated by the GTPase Rab5, a key regulator of early endocytosis, as blocking Rab5c activity in wild-type embryos phenocopies slb/wnt11 mutants, and enhancing Rab5c activity in slb/wnt11 mutant embryos rescues the mutant phenotype. In addition, we find that Wnt11 and Rab5c control the endocytosis of E-cadherin and are required in mesendodermal cells for E-cadherin-mediated cell cohesion. Together, our results suggest that Wnt11 controls tissue morphogenesis by modulating E-cadherin-mediated cell cohesion through Rab5c, a novel mechanism of Wnt signaling in gastrulation."
- Mike's comments:
So, it seems that they're saying that wnt11 persistently occupies the receptor and continues to carry out its signaling function.
- All: There is 1 annotation to GO:0045121 "membrane raft" (Drosophila wingless, PMID 15166250). I've propagated it to the entire Wnt1/Wnt3 clade, but haven't found any other literature to support such an annotation for any Wnt. Comments would be appreciated.
- Curator answer: My understanding is that membrane rafts are quite specialised structures, so I would not annotate to the whole clade if there is no literature to support this in other species -- Varsha
- from the wikipedia description of lipid rafts (http://en.wikipedia.org/wiki/Lipid_raft) I think that probably ISS of receptors to lipid rafts is OK. -- Ruth
- If it is agreed that ligands can be annotated to the membrane, then I agree with the Wnt1/3 clade being annotated to membrane raft -- Varsha
- 1)The description of "lipid rafts" is not well-portrayed in the GO definition of "membrane raft." Wikipedia's is a more detailed/useful description; if accurate, maybe we should ask for a revision of the definition of membrane raft. 2) Regarding the query about "plasma membrane" as an annotation: Other than when I added the background info to the minutes from the meeting, there has been no further discussion of the issue, so I think it is unresolved. Personally, I think the definition of plasma membrane does include a ligand bound to a receptor, in part because there is a child term GO:0031236 "extrinsic to external side of plasma membrane, in periplasmic space" that seems at least as loosely bound to the membrane if not more so. It would be a true path violation if this term were not part of the plasma membrane. -- Mike
- Please note: Even though there is a major reconfiguration of the transcription part of the ontology underway, please consider using more specific terms whenever possible. Examples:
GO:0010628 "positive regulation of gene expression" OR GO:0045449 "regulation of transcription" GO:0043193 "positive regulation of gene-specific transcription" GO:0010552 "positive regulation of gene-specific transcription from RNA polymerase II promoter"
or the corresponding negative regulation terms if appropriate.
- Mouse: Do you recommend propagating the Wnt10a GO:0014033 "neural crest cell differentiation" IDA from PMID 17286598 (MGI 3712614) to the rest of the Wnt10a's? I can't access the fulltext paper.
- Curator answer:Yes, to the organisms which have odontoblasts (“a biological cell of neural crest origin“).
- Mouse: Should the Wnt7a GO:0016055 "Wnt receptor signaling pathway" IDA from PMID 19497282, "Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells," actually be to GO:0060071 "Wnt receptor signaling pathway, planar cell polarity pathway"?
- Curator answer:The paper talks about how Wnt7a alter the ratio between asymmetric and symmetric cell divisions of satellite stem cells in vitro. I only feel comfortable to annotate it to GO:0030010: “establishment of cell polarity” and GO:0016055 "Wnt receptor signaling pathway" since I don’t see any evidence from the paper to say it “activated receptors signal via downstream effectors including C-Jun N-terminal kinase (JNK) to modulate cytoskeletal elements and control cell polarity”, as it states in the definition of GO:0060071.
- Also in the definition of GO:0001736 “establishment of planar polarity”, it particular says epithelium. Since GO:0060071 is a child of GO:0001736, I am assuming that the “epithelium” applies to GO term GO:0060071. However, the paper uses satellite stem cells. That’s another reason I didn’t feel comfortable to use specific planar cell polarity term.
- Mouse: For Wnt10b GO:0043586 "tongue development," would you prefer the child term GO:0061196 "fungiform papilla development"? The reference (PMID 17284610) states "Shh expression in fungiform papillae and formation of normal mature fungiform papillae depend on signaling through Wnt and beta-catenin."
- Curator answer:Yes, change made in MGI. The child term was added after the paper had been curated.
- Mouse: For Wnt6, instead of GO:0048754 "branching morphogenesis of a tube" from PMID 11948913, would you prefer GO:0001658 "branching involved in ureteric bud morphogenesis"? Instead of GO:0035148 "tube formation," would you prefer GO:0072079 "nephron tubule formation"?
- Curator answer:Yes. Yes.
- Mouse: Please verify the Wnt1 GO:0001658 "branching involved in ureteric bud morphogenesis" IGI from PMID 16054034. The paper says that Wnt1 can substitute fror Wnt9b in urogenital development, but does that mean that that is the natural role of Wnt1?
- Curator answer:The paper shows Wnt1 expression was sufficient to rescue mesonephric and metanephric tubule induction, as well as caudal extension of Müllerian duct, in Wnt9b−/− mutants. No data available from this paper whether Wnt1 expresses there. To me it’s a curator’s judgment to make that annotation. I would suggest PAINT leave it alone, not to propagate.
- Mouse: Wnt7b has an IMP to GO:0032364 "oxygen homeostasis" from PMID 18367557. Is this due to its lung development phenotype? Is Wnt7b directly involved in oxygen homeostasis, or is this a downstream effect?
- Curator answer:
- Is this due to its lung development phenotype?
- Due to cyanosis which is associated with “deoxygenated hemoglobin in blood vessels”.
- Is Wnt7b directly involved in oxygen homeostasis, or is this a downstream effect?
- If I remember correctly, I could not make any conclusion based on the data.
- Mouse Wnt7b: Instead of GO:0042476 "odontogenesis," would you prefer GO:0042475 "odontogenesis of dentine-containing tooth"?
- Curator answer:Yes.
- Mouse: Wnt9b has IMP's to GO:0048701 "embryonic cranial skeleton morphogenesis" and GO:0060021 "palate development," both from PMID 16054034. Do you want to request some sort of cross-product, like "embryonic palate morphogenesis"?
- Curator answer:see David's comments at the end of the page.
- Mouse: Would you like to make an annotation to GO:0035567 "non-canonical Wnt receptor signaling pathway" for Wnt11 based on PMID 17767158, "Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFbeta2"?
- Curator answer:Was waiting for the new term. Yes, change made in MGI.
- Mouse: Please double-check the Wnt4 GO:0072034 "positive regulation of renal vesicle formation" annotation from PMID 11507767. The paper seems to be about Wnt2.
- Curator answer:The Wnt4 one is right, but it is a reconstitution expt. The paper supports that Wnt4 regulates induction while Wnt2b regulates the branching.
Mouse and Rat
- Rat and Mouse: Mouse Wnt7a has an annotation to GO:0050770 "regulation of axonogenesis." Rat Wnt7b has an annotation to GO:0032536 "regulation of cell projection size" from PMID 18177422; the abstract of this paper states, "Ectopic wnt7b overexpression was sufficient to rescue neurite outgrowth in NGF-treated p53-silenced PC12 cells." Is this sufficient to generalize "regulation of axonogenesis" to both Wnt 7a and -7b? Put another way, are PC12 "neurite outgrowths" sufficiently axon-like that this is probably the same process?
- Curator answer:MGI made the annotation according to paper PMID 9405095. It seems OK to me to generalize "regulation of axonogenesis" to both Wnt 7a and -7b.
- Zebrafish: Should either of the GO:0030178 "negative regulation of Wnt receptor signaling pathway" IGI's be to the child term GO:0090090 "negative regulation of canonical Wnt receptor signaling pathway"?
- Response:Yes, both should. I'll get to it tomorrow. Note to self: update ZDB-PUB-070523-22 -Doug
- Zebrafish: wnt8a and -8b have annotations to GO:0001654 "eye development." Please specify that this is "camera-type" (GO:0043010) and consider more specific child terms such as "embryonic" (GO:0031076), "morphogenesis" (GO:0048593), or both (GO:0048596).
- Zebrafish: Does PMID 18798004, "A role for planar cell polarity signaling in angiogenesis," justify an wnt5 annotation to GO:0060071 "Wnt receptor signaling pathway, planar cell polarity pathway"?
- Zebrafish: Instead of the wnt5b GO:0010172 "embryonic body morphogenesis" annotation from PMID 9598355, would you prefer GO:0035121 "tail morphogenesis," or were you trying to stress the "embryonic" aspect of the annotation? Does 35121 imply that the process is embryonic? Similarly, can you specify an organ/tissue for the wnt8b GO:0009880 "embryonic pattern specification" annotation from PMID 15366005?
- Worm: Is signaling through Ror a new pathway? See PMID 19855022.
Questions for ontology curators
- Is there a plan to make GO:0005110 "frizzled-2 binding" a child of GO:0005109 "frizzled binding" as described in SF # 3025937?
- Does GO:0060070 "canonical Wnt receptor signaling pathway" has_part "regulation of gene expression" or something like it?
- Should GO:0060071 "Wnt receptor signaling pathway, planar cell polarity pathway," defined as "The series of molecular signals initiated by binding of a Wnt protein to a receptor on the surface of the target cell where activated receptors signal via downstream effectors including C-Jun N-terminal kinase (JNK) to modulate cytoskeletal elements and control cell polarity," has_part GO:0007254 "JNK cascade" or something like it?
- Should there be a more direct relationship between GO:0046330 "positive regulation of JNK cascade" and GO:0043507 "positive regulation of JUN kinase activity"? They are both children of GO:0046328 "regulation of JNK cascade."
- There are some "development" terms that have "embryonic" children, and some that don't. For those that don't, is it assumed/understood that the processes occur in the embryo? Would these be the sort of terms that it should be possible to auto-request?
- The lack of embryonic children under development terms simply means that we have not added them. It does not assume that the process always or completely occurs in the embryo. -dph