Cilia: new terms and links - cellular component branch

[gocentral]

We are in contact with John van Dam, Toby Gibson and colleagues to add/revise terms related to cilia (CC and BP). Here is a first list of suggested edits from John:

"...In the end I've removed a lot of terms from my list because I found out they already existed as part of the axoneme term, which itself was not connected to the cilium. I've missed these terms using the graphical viewer in OBO-edit. Please find attached an excel file with the new terms, a short definition, reference data and relationships. I've also added some new connections for existing terms as well as identified some issues that need some rewiring of the terms. I am sure that in terms of is_a and part_of relationships there are more issues to solve. I will try and figure those out this December, as well as figure out the biological processes part. One of these things is the fact that some terms define areas through which other components cross, like "ciliary transition zone" and "axoneme", in the excel file I've made "axoneme" part_of "ciliary transition zone", but I'm not quite sure if it is the way to go."

The excel file is called "New GO terms - Nov2013" and is attached.

Paola

Reported by: paolaroncaglia

Original Ticket: geneontology/ontology-requests/10553

[gocentral]

Hi John (and Karen),

Hope you're having a good summer! Back to the issue of "Currently, 'ciliary transition zone' is part_of 'nonmotile primary cilium': is this correct or is it too restrictive?", based on John's reply dated (ahem) 2013-12-23 and on his provided reference, I deleted that link. Hope to be in touch soon with more edits...

Thanks, Paola

Original comment by: paolaroncaglia

[gocentral]

I've had a great summer! Thank you! Hope yours was great as well? I am glad to see that the TZ now also is part of the motile cilium :-)

Original comment by: johnvandam

[gocentral]

Thanks John. Yes all well! Speak soon. Paola

Original comment by: paolaroncaglia

[gocentral]

Following email discussions with experts, to make ciliary terms applicable also to species such as Giardia:

Moved 'cilium' up to generic 'organelle' (was 'membrane-bounded organelle'); edited def. accordingly; (*)

Added def. comments to 'ciliary basal body' and 'centriole' to highlight commonalities and differences; edited def. of cilium accordingly; () and (*)

Added def. comment to 'axoneme' (***)

Details of changes:

(*) 'cilium': "A specialized eukaryotic organelle that consists of a filiform extrusion of the cell surface and of some cytoplasmic parts. Each cilium is largely bounded by an extrusion of the cytoplasmic (plasma) membrane, and contains a regular longitudinal array of microtubules, anchored to a basal body." and added a definition comment: "In most eukaryotic species, intracellular sub-components of the cilium, such as the ciliary base and rootlet, are located near the plasma membrane. In Diplomonads such as Giardia, instead, the same ciliary parts are located further intracellularly."

(**) definition comment for 'ciliary basal body' and 'centriole': "In most eukaryotic cells, 'ciliary basal body' (GO:0036064) and 'centriole' (GO:0005814) represent a common entity that cycles through its function in cell division, then ciliogenesis, then cell division again. However, these structures are modified extensively as they transition into each other, and may contain different proteins, specific to each component."

(***) definition comment for 'axoneme': In Diplomonads species such as Giardia, the axoneme may extend intracellularly up to 5um away from the plane of the plasma membrane.

Original comment by: paolaroncaglia

[gocentral]

Dear John (and Karen),

Hi, I hope all is well with you! It’s been some time since we last ‘spoke’, things have been quite busy my end, but of course this project isn’t forgotten. I’m writing to discuss motile vs. non-motile cilia. This follows from a request from one of my fellow GO editors who’d like a new term for ‘non-motile cilium’, to use in cases such as the olfactory knob that has multiple non-motile cilia. To recap, the current situation in GO is:

cilium

--- motile cilium

--- primary cilium ------ motile primary cilium
------ nonmotile primary cilium

I.e. we don’t have a term for non-motile, non-primary cilium.

I don’t see any reason not to add a new term for ‘non-motile cilium’ - there seem to exist at least several cases of cell types that have more than one cilium where the cilia are non-motile. Would you agree? (The existing term ‘nonmotile primary cilium’ would then get ‘non-motile cilium’ as an additional parent.)

From the point of view of GO, strictly speaking, it feels to me like the one and only real distinction should be the functional one between motile and non-motile cilia. The fact that a cell has one cilium (‘primary cilium’) or several/many cilia feels like a secondary distinction inherent to the cell morphology rather than to the ciliary function. But I presume that both distinctions are relevant and useful for cilia researchers, so I’d be fine with keeping both. Just wanted to be sure.

Minor point: should the primary name be ‘non-motile’ or ‘nonmotile’? I think the community usage points towards ‘non-motile’, so I’d use that and keep ‘nonmotile’ in exact synonyms.

Lastly, for purposes of automatic classification within GO, my fellow editor suggested to add this link:

‘motile cilium’ capable_of_part_of ‘cilium movement’

Let me know if you’d have any concern about this.

Thanks,

Paola

Original comment by: paolaroncaglia

[gocentral]

Hi Paola,

I think my question would be whether the structure of the multiple non-motile cilia are different from that of non-motile primary cilia. If there's something unique that occurs in the olfactory knob, then there's definitely a need with respect to annotation to have a distinct term.

For example, the motile primary cilia of the node (also referred to as nodal cilia) have a different structure from "regular" motile cilia. Then we have some unique things like "kinocilia" which which is found in the cochlea and associated with organization of stereocilia structures, so there are definitely some unique processes and associations for kinocilia that are easiest to capture with specific terms, even though in many ways the kinocilium is a primary cilium.

I haven't encountered anything about multiple non-motile cilia in the olfactory knob, so I don't have any specific knowledge in that area.

-Karen

Original comment by: krchristie

[gocentral]

Hi Paola,

The Fisch and Dupuis-Williams 2011 review "Ultrastructure of the cilia and flagella - back to the future" looks like it has a very useful section, subtitled "Basic axonemal structure", that may help sort out the issue of how to group cilia based on structure, either 9+0 or 9+2 with or without other structures correlated with motility.

-Karen

Original comment by: krchristie

[gocentral]

Hi again,

I was trying to annotate a protein found in the axonemal central apparatus and did not find any appropriate terms for this. There is just "axonemal central pair" which seems appropriately to be specifically the two central pair microtubules but not the associated proteins of the central apparatus. So, both to meet my current needs and to better represent the axonemal structure, here are some suggested new terms, as well as some suggestions for existing terms.

-Karen

1. some changes to this existing term: term: axonemal central pair - GO:0097540 Def: Part of the axoneme consisting of the inner two microtubule doublets of the 9+2 axoneme occurring in most motile cilia. is_a: axoneme part ADD: part_of: GO:new1 see also comment 4 about the "axonemal microtubule" term
2. inconsistency in term names - "radial spoke stalk" vs. "radial spokehead" I think we should change "radial spokehead" to "radial spoke head"
3. We have the term "nexin complex". Inaba 2011 says "interdoublet or nexin links are present as connective structures between each doublet microtubule", so it looks like this represents the structure labelled as a "interdoublet link" in the Inaba review. Searching PubMed for "nexin complex" produces over a thousand papers, most of which do not seem cilia specific, but instead many things like "Retromer and sorting nexins in endosomal sorting"Thrombin inhibition by the serpins", with a few cilia refs in the mix. I think we might want to consider slightly modifying the main name of this term to be more specific, maybe "axonemal nexin link". We could also add "axonemal interdoublet link" as a synonym, with PMID:9295136; PMID:21586547, PMID:22683354, PMID:21728999 as an additional def dbxrefs.
4. I am finding the term "axonemal microtubule" a bit weird in that both "axonemal central pair" and "axonemal outer doublet" have has_part relationships to this term, despite the fact that the structure of the outer doublet microtubules are rather different than that of the inner pair microtubules, which are singlet microtubules, not doublets. It seems like it might not be very good to say that both the central pair and the outer doublet share a common part when in fact, they do not share the same structure, so I think we should consider removing these has_part relationships. Since I am suggesting adding terms for the C1 and C2 tubules of the central pair, with the appropriate part_of links to the central pair term, that might be sufficient. However, if you think it's appropriate, I think it would be true to give has_part relationships from "axonemal outer doublet" to both the "A tubule" and "B tubule" terms and from the "axonemal central pair" term to the "C1 tubule" and "C2 tubule" terms. That would result in reciprocal part_of and has_part relationships. I don't know if we do that, but I think it would be accurate in this case.
5. New terms

term: axonemal central apparatus - GO:new1 Def: Part of the 9+2 axoneme, that occurs in most motile cilia, consisting of two single microtubules and their associated structures which include the central pair projections, the central pair bridges linking the two tubules, and the central pair caps which are attached to the distal or plus ends of the microtubules. Def dbxref: PMID:9295136; PMID:21586547 is_a: axoneme part

term: axonemal central bridge - GO:new2 Def: Part of the 9+2 axoneme, that occurs in most motile cilia, consisting of the two bridges which connect the central pair of microtubules. Def dbxref: PMID:9295136; PMID:21586547 is_a: axoneme part part_of: GO:new1

term: axonemal central pair projection - GO:new3 Def: Part of the 9+2 axoneme, that occurs in most motile cilia, consisting of the projections off of the central pair of microtubules Def dbxref: PMID:9295136; PMID:21586547 is_a: axoneme part part_of: GO:new1

term: C1 tubule - GO:new4 Def: One of two tubules present in the axonemal central pair that is distinguishable from the C2 tubule by the presence of differing protein components of the projections. Def dbxref: PMID:9295136; PMID:21586547 is_a: axonemal microtubule (GO:0005879) part_of: axonemal central pair - GO:0097540

term: C2 tubule - GO:new5 Def: One of two tubules present in the axonemal central pair that is distinguishable from the C1 tubule by the presence of differing protein components of the projections. Def dbxref: PMID:9295136; PMID:21586547 is_a: axonemal microtubule (GO:0005879) part_of: axonemal central pair - GO:0097540

Original comment by: krchristie

[gocentral]

Hi Karen,

Many thanks for your detailed and precious feedback. Unfortunately at the moment I don't have a chance to work on this, but will try to implement as soon as possible. Note for self: I will also follow-up with John Van Dam as I'm not 100% sure he's still on this project.

Paola

Original comment by: paolaroncaglia

[gocentral]

Hi Paola,

If it would help, I could do the new terms by TermGenie. Then all you would need to do is the other changes.

-Karen

Original comment by: krchristie

[gocentral]

Hi Karen,

That's a good idea actually :-) Would you mind submitting the new terms via TG next week? As I'm on duty next week. So I can tie it all together. I'm a bit swamped this week. But if you need them more urgently, let me know. Thanks!

Paola

Original comment by: paolaroncaglia

[gocentral]

Hi Paola,

Sorry, I totally forgot to submit these earlier in the week, so I'm just going to do them now so I can start using them soon.

• ID: GO:1990716 Label: axonemal central apparatus
• ID: GO:1990717 Label: axonemal central bridge *: (still needs part_of rel to GO:1990716)
• ID: GO:1990718 Label: axonemal central pair projection *: (still needs part of: GO:1990716)
• ID: GO:1990719 Label: C1 axonemal microtubule
• ID: GO:1990720 Label: C2 axonemal microtubule

Note: I tried to submit the label "C1 tubule" to follow the existing names of the "A tubule" and "B tubule" terms, but received the error that "The label is too short." I switched to this name, which might be better, but if we use these longer names for the C1 and C2 tubules, I think we should modify the names of the A and B tubule terms also for consistency.

thanks,

-Karen

Original comment by: krchristie

[gocentral]

Hi Karen,

I'm committing your terms, and adding the GOC:cilia dbxref for internal reference. Yes, I'll edit the labels for A and B tubules for consistency.

Later,

Paola

Original comment by: paolaroncaglia

[gocentral]

I also added 'C1 tubule' and 'C2 tubule' as broad synonyms.

Original comment by: paolaroncaglia

[gocentral]

Note for self: I still need to address my own comment from 2015-03-12, along with Karen’s replies to that. I also still need to take care of Karen’s requests 1 to 4 from 2015-03-13 (request 5 for new terms is all done now).

Original comment by: paolaroncaglia

[gocentral]

Hi Paola,

I have realized I need a BP term that is specific to the assembly of the axonemal central apparatus. I have submitted already via a TermGenie template:

ID: GO:1904158 Label: axonemal central apparatus assembly

In addition to the relationships created by TG:

is_a: GO:0022607 {is_inferred="true"} ! cellular component assembly intersection_of: GO:0022607 ! cellular component assembly intersection_of: results_in_assembly_of GO:1990716 ! axonemal central apparatus relationship: results_in_assembly_of GO:1990716 {is_inferred="true"} ! axonemal central apparatus

it would be good if this term was part_of "axoneme assembly".

thanks,

-Karen

Original comment by: krchristie

[gocentral]

Hi Karen, done. Thanks, Paola

Original comment by: paolaroncaglia

[paolaroncaglia]

Wrapping up pending to-do items: 1) added links: ciliary base has_part ciliary transition zone ciliary base has_part ciliary transition fiber ciliary shaft has_part axoneme axonemal central pair part_of axonemal central apparatus axonemal outer doublet has_part A axonemal microtubule axonemal outer doublet has_part B axonemal microtubule axonemal central pair has_part C1 axonemal microtubule axonemal central pair has_part C2 axonemal microtubule 2) removed (now) redundant has_part links from axonemal central pair and axonemal outer doublet 3) changed radial spokehead into radial spoke head 4) changed nexin complex into axonemal nexin link

[paolaroncaglia]

Dear @JohnvanDam and @krchristie,

This ticket was the first one containing John’s initial suggestions for ciliary component edits, and where we started discussion with Karen too. I went over it again in detail, and made sure that every suggestion we agreed on was implemented. (So you may ignore all of the previous comments in this ticket.) There are only two pending points. One is about types of cilia (I’ll create a separate ticket for that, so let’s leave these aside for now). The other is about a link that John suggested. Could you please provide feedback on the following:

In his initial set of suggestions, John mentioned this one: GO:0034464 BBSome part_of intraflagellar transport particle (GO:0030990) Note that GO:0030990 has since been renamed intraciliary transport particle. Based on the current definitions of the two terms BBSome = A protein complex that associates with the primary cilium and is involved in cilium biogenesis; consists of seven conserved proteins: BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9. intraciliary transport particle = A nonmembrane-bound oligomeric protein complex that participates in bidirectional transport of molecules (cargo) along axonemal microtubules. John’s suggested link sounds a bit weird to me. Do you agree that we should drop this?

Note for self: once this is resolved, I can close this ticket.

[JohnvanDam]

Hi Paola,

The BBSome definition appears to be outdated, hence the confusion.

PMID: 26498262 "The BBSome, a complex comprising eight BBS proteins, moves in association with IFT trains through cilia (Figure 2) 11, 20, 21, 22 and 23." "The BBSome, comprising at least seven Bardet–-Biedl syndrome (BBS) proteins and BBIP10, appears to be a substoichiometric component of IFT trains."

But reading a little more it appears to become a bit muddled.

Blacque at al. show that the BBSome is required for IFT-A and IFT-B integrity (http://genesdev.cshlp.org/content/18/13/1630) But this does not necessarily mean it is "part of", though highly suggestive.

Williams et al. find it is an integral part of IFT in mammalian olfactory neurons. (doi:10.1038/ncomms6813)

But Lechtreck et al. describe the BBSome in Chlamydomonas reinhardtii as "IFT cargo required for export of specific signalling proteins" (J. Cell Biol., 187 (2009), pp. 1117–1132). I think that the description of the BBSome as "cargo to carry other cargo" is a bit weird. The complex might not directly provide the directional locomotion, but I think that as an consistent constituent of the IFT train it is therefore "part_of".

I'll do a little more digging later this week (also to make that NPHP def) once I send my paper out (again). Sorry for the hold up.

Cheers, John

[paolaroncaglia]

OK, thanks @JohnvanDam , I'll wait before adding the link.

[krchristie]

Hi Paola and John,

Coincidentally, the IFT complex and the BBSome complexes are both things where I have annotated the mouse genes fairly completely, so I understand this somewhat well, though my impression is that there are still some open questions about exactly how the BBSome functions.

Anyway, my impression is that the BBSome has several roles, one of which is as a cargo adaptor for IFT trains. However, it is not the only cargo adapter, and the other cargo adaptors, e.g. Tulp proteins, that I know of are considered to be part of IFT.

This paper: Avidor-Reiss T, Leroux MR. Shared and Distinct Mechanisms of Compartmentalized and Cytosolic Ciliogenesis. Curr Biol. 2015 Dec 7;25(23):R1143-50. doi:10.1016/j.cub.2015.11.001. Review. PubMed PMID: 26654377 says: "Comparative genomics therefore affords tremendous predictive power when contrasting highly divergent or closely related organisms that display cellular and morphological differences. It is within this framework that we consider how different macromolecular complexes, that is, the transition zone (TZ) and the core intraflagellar transport (IFT) machinery with its associated Bardet-Biedl syndrome complex (BBSome), are differentially employed to support two distinct categories of ciliogenesis — compartmentalized and cytosolic — and the different types of cilia present across diverse eukaryotes."

This seems consistent with the way I have seen the IFT machinery described, as being composed of IFT-A and IFT-B, and then IFT associates with many various cargo adaptors, of which BBSome is one.

So, at the moment, I am not in favor of adding GO:0034464 BBSome part_of intraflagellar transport particle (GO:0030990)

-Karen

[JohnvanDam]

Since the uncertainty in literature I am inclined to agree with Karen on not adding the link at this point, until the literature will become more definitive on this point. Just to gouge some perspective from others I've asked one of my collaborators who has worked on IFT and BBSome for his opinion. I will take into account that his view may be not be representative, but I hope his reply will have some leads to interpret/search for additional literature.

The BBSome term definition is outdated however, so we might as well try to fix/update that a little. More on this in a hour or so.

[JohnvanDam]

From Oliver Blacque:

Hi John

The BBSome is not considered an intergral 'core' part of IFT. The BBSome complex absolutely >associates with IFT complexes in some way (as an IFT-A/B adaptor or cargo of sort), but they are >biochemically and functionally distinct.

Cheers Ollie

This still leaves papers like PMID: 2550414 which state: "We identify Bardet-Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles." But I think it is better to err on the side of caution and let the scientist battle this out a little more before (and if!) we make the connection in GO.

[paolaroncaglia]

Thanks @krchristie and @JohnvanDam (and Oliver),

Summing up, I will not add the part_of link GO:0034464 BBSome part_of intraflagellar transport particle (GO:0030990). Instead, I updated the def of GO:0034464 BBSome, and added a part_of link to ‘cilium’. The revised stanza is below for reference. Closing now.

[Term] id: GO:0034464 name: BBSome namespace: cellular_component def: "A ciliary protein complex involved in cilium biogenesis. It consists of at least seven Bardet–-Biedl syndrome (BBS) proteins and BBIP10. It moves in association with IFT trains through cilia (likely as an IFT-A/B adaptor or cargo), and is required for the integrity of IFT-A and IFT-B." [GOC:BHF, GOC:cilia, PMID:15231740, PMID:17574030, PMID:26498262] synonym: "Bardet-Biedl syndrome complex" EXACT [] is_a: GO:0043234 ! protein complex relationship: part_of GO:0005929 ! cilium