Kidney - Loop of Henle Cocuration

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  • Dr. Yasmin Alam-Faruque - EBI. email:
  • Dr. Rebecca Foulger - EBI. email:
  • Dr. Fiona McCarthy - AgBase. email:

Genes of interest to start annotating

This table represents a GO annotation starting list for this project showing the UPKB accession number for each gene and an approximate number of papers from a quick pubmed search for the gene name and the species and kidney function. Please feel free to start annotation whenever suits you and to add comments for discussion and completion date etc. If you come across further genes of interest please add them to the list on this wiki and send them to me so that I can update the xls gene list.

Involvement in kidney function Mouse Human Rat Chicken Xenopus Laevis Xenopus tropicalis Completed Comments*
Tesc Q9JKL5/ 1 Q96BS2/ 1 IPI00769039/ - A0AVX7/ 1 Q5U554/ 1 Q0V9B1/ - yes [YAF] PMID 19345287 state (pg 278, top right) that a lack of kidney expression by immunocytochemistry in mice embryos suggests that TESC might not have a significant role in kidney[RF].

PMID 11145610 states that TESC mRNA was present in mouse fetal testis restricted to the testicular cords but was not expressed in the ovary or metanephros. Col9a3 was present at low levels in female and male gonads at 11.5 days and thereafter upregulated in male gonads only and expression was restricted to testicular cords; Renin was localized in cells of the interstitium and cells at the border between the gonad and mesonephros (from abstract and Fig.6 A-L ISH) [YAF 26/08/09]

Slc23a1 Q9Z2J0/ 3 Q9UHI7/ 7 Q9WTW7/ 4 B9VMA9 (Slc23a2)/ 1 -/ 1 B0JZG0 (Slc23a2)/ - There's no chicken or Xenopus Slc23a1 TrEMBLs yet: Slc23a2 entries are closest match, tho according to PMID 17689499, Slc23a1 (SVCT1) is expressed in epithelial systems (eg kidney), whereas Slc23a2(SVCT2) is more expressed in metabolic tissues (eg pancreas, brain, adrenals)[RF].

PMID 17258485 demonstrates presence of chicken-specific SVCT1 mRNA (via RT-PCR)in both cultured and native proximal tubule cells using primers derived from chicken ESTs and hence demonstrates vitamin C transport [YAF 28/08/09]

Ctnnb1 Q02248/ 49 P35222/ 84 Q9WU82/ 15 O42486/ 1 P26233/ 4 Q28GC2/ -
Lamb1-1 P02469/ 1 P07942/ 1 P15800(Lamb2)/ - O57484/ - Q5XHI6/ - B3DLV1/ - yes [YAF 10/11/09] PMID 12631063 shows that murine laminin-1 is normally downregulated in early stages of glomerular development and is reexpressed in a murine model of Alport disease becoming concentrated in the glomerular basement membrane projections typical of this disorder - maintains expression of collagen alpha1 and alpha2(IV). hence collagen alpha3(IV) is involved in glomerular basement membrane development since in col4a KO mice there is an abnormal GBM characteristic of immature glomeruli. PMID 16041630 shows abnormal basement membrane in the inner ear and kidney of the Mpv17-/- KO mice, therefore Mpv17 is involved in glomerular basement membrane development and inner ear development. PMID 16631359 is just an article on production of mAb against mouse laminin alpha and beta chains but shows expn in adult kidney [YAF 10/11/09].
Egr1 P08046/ 3 P18146/ 9 P08154/ 6 O73691/ - Q6GQH4/ - A4II20/ - yes [YAF 17/11/09] No kidney expression or function for Xenopus Egr1. Induced during mesoderm induction [REF 16/11/09]. Not much for mammalian kidney expression or function. PMID 8530399 shows transcriptional activation/repression of murine egr1 by WT1. PMID 12689920 shows increase in murine egr1 expression by insulin and glucose in murine vascular endothelial cells. PMID 14979875 investigates interaction between human NFATc1 and Sp1/Sp3/EGR1 regulating MT-MMP transcription by glomerular mesangial cells. [YAF 17/011/09]
Pou3f3 (Brn1) P31361/ 3 P20264/ 2 Q63262/ - Q52HB4/O73861/ - P70030 (pou3f2-B)/ - A1L0Z1 (Pou3f4)/ - yes [YAF] PMID 12925600 shows that Brn1 is essential for kidney nephron development and function:-need to request many new terms (see below in Comments section [YAF 18/09/09]. PMID 15249135 shows expression of Brn1 in mouse cortical plate of brain - no functional study in this paper therefore not annotated[YAF 17/11/09].
Id2 P41136/ 4 Q02363/ 1 P41137/ 1 O73933/ - Q9YGL0/ - Q6PBD7/ - Expressed in the developing pronephros in X.laevis (PMID 7734394 and PMID 14651922) but no functional role examined yet[REF 16/11/09].

Id proteins have been shown to disrupt pax interactions with target DNAs, which may explain their role in kidney development (summary from PMID 14651922 based on results in PMID 11134340) [REF 17/11/09]. PMID 7655079 looks at mId3 expression during development of metanephric kidney, tooth development, vertebrate column development and CNS development, so annotated mouse Id3 P41133 to terms with IEP ev code [YAF 17/11/09]. For mouse Id2: PMID 12456807 - not kidney specific but important for mammary gland alveolar epithelial cell differentiation (NTR). PMID 8922523 looks at mRNA expn of mouse Id1/2/3/4 during mouse embryogenesis - Id1-3 seem to be expressed during development of multiple tissues inc. lung/kidney/heart/teeth/cartlage and bone/ vascularization/glandular structures; Id4 seems only to be expressed in the developing neuronal tissues and in ventral epithelium of developing stomach - did not annotate into P2G as it is mRNA expn data?[YAF 24/11/09]

Cdh11 P55288/ 3 P55287/ 1 Q9JIW2/ 1 O93319/ - O93264/ - Q5EAM2/ -
Aldh1l1 Q8R0Y6/ - O75891/ - P28037/ - O93344/ - Q6GNL7/ - Q63ZT8/ -
Tfap2b Q61313/ 3 Q92481/ 3 P58197/ - O93346/ - Q66J14/ - Q28C75/ -
Ttr P07309/ 1 P02766/ 4 P02767/ - P27731/ 1 Q9W649/ 3 A4QNN7/ - Xenopus ttr shows some kidney expression but there are no papers relating to it's role in the kidney.
Ptn P63089/ 2 P21246/ 1 P63090/ 3 P32760/ - P48532/ - A4IH83/ -
Ccnd1 P25322/ 21 P24385/ 24 P39948/ 15 P55169/ - P50755/ - Q6GLD3/ -
Irx3 P81067/ 2 P78415/ - - Q9PUR3/ - O42261/ 1 Q6NVN3/ - (Not on GUDMAP LoH list) comparitive paper PMID 17875669 looking at expression of Irx1, 2 and 3 in the mouse LOH (pg 2361-2362) and the function of Xenopus irx3 in the pronephron:

Expression patterns for Xenopus and mouse (PMID 17875669) suggest a function for Irx3 in patterning the nephron by specifying pronephron intermediate tubule and metanephron Henle's loop fates respectively. The function in frogs is confirmed with knock-outs [RF, 15/09/09].

PMID 18715948 looks at Irx1 and Irx2 in Xenopus pronephros development. .

Irx2 P81066/ 1 Q9BZI1/ - - Q9PU52/ - Q6DCQ1/ - Q66IK1/ - " (Not on GUDMAP LoH list) Need to be slightly cautious about nomenclature for the irx proteins. Human irx3 is called irx1 in some submissions, and mouse irx2 is called irx6 in PMID 10704856, for example. [REF 24/09/09]
Irx1 P81068/ 2 P78414/ - - Q9I9C5/ - Q9YGK8/ 1 Q6F2E3/ - " (Not on GUDMAP LoH list)

PMID 17875669 show Xirx1 is dispensable for kidney development, but PMID 18715948 show Xirx1 and Xirx3 are required early on to maintain kidney field identity, and then later for formation of the intermediate tubule (contained in the LOH in mammals) [REF 25/09/09]

Pax2 P32114/ 40 Q02962/ 34 IPI00364303/ 4 Q9PTX1/ 3 O57685+O57682/ - Q28IR6/ - (Not on GUDMAP LoH list)
Pax8 Q00288/ 23 Q06710/ 22 P51974/ 1 -/ 2 Q9PUK5/ 1 A0JMA6/ -
Bmp4 P21275/ 36 P12644/ 23 Q06826/ 6 Q90752/ - P30885/ 1 Q90YD6/ - (Not on GUDMAP LoH list)
Cited1 P97769/ 3 Q99966/ 2 Q4V8P1/ 1 -/ 1 -/ - -/ - yes [YAF 10/11/09] (Not on GUDMAP LoH list) PMID 15843474 shows that rat Cited1 is a bifunctional transcriptional cofacor that regulates early nephronic patterning - it inhibits metanephric mesenchyme to epithelium transition and is also able to block UB branching. PMID 16864582 + PMID 11581164 = human CITED1. PMID 14673158 = mouse cited1 involved in placental development. PMID 17615577 mouse cited 1 and cited 2 not required for nephrogenesis.
Cited2 O35740/ 1 Q99967/ 1 Q99MA1/ - Q9DDW4/ 1 Q5XGW7/ - Q6NX30+Q28GT4/ - yes [YAF 10/11/09] PMID 15051727 shows that human CITED2 interacts with the ligand binding domain of rat PPARA and acts as a coactivator for rat PPARA. Also did microarray analysis to show the effect of CITED2 on gene expression.

No papers for X.laevis or X.tropicalis [REF 16/11/09].

c-myc P01108/ 65 P01106/ 85 P09416/ 19 P01109/ 1 P06171/ 3 Q6P1T1/ - (Not on GUDMAP LoH list) PMID 19161241 investigates role of mouse c-myc in nephrogenesis - c-myc mutants had small kidneys and causes renal hyperplasia [YAF 06/11/09].
Wt1 P22561/ 120 P19544/ 272 P49952/ 33 Q9I8A0+Q9I8A1/ 6 B7ZSG3+P79958/ 6 B5DE03/ - (Not on GUDMAP LoH list)

Xwt1 plays a role in glomus (pronephric filter system) development; may repress tubule (and duct?) gene expression in the region of the pronephros fated to become the glomus PMID 8725280 PMID 9758706 [REF 24/11/09]. Most mammalian WT1 papers I have annotated are mainly investigating it's transcription repressor activity of certain genes. PMID 19050011 investigates involvement of WT1 and BASP1 in podocyte differentiation (NTR) [YAF 26/11/09].

Osr1/Odd1 Q9WVG7/ 6 Q8TAX0/ 4 B0K011/ - -/ 2 Q32NK7+Q0IHB8/ 1 Q66JF8/ - (Not on GUDMAP LoH list)(Found when doing a PM search on kidney development). PMID 16790474 and PMID 18835385 have led to many new terms needing to be created. Also interestingly, reports that in wild type mice there are 2 types of mesonephric tubules that develop: anterior tubules fuse with the nephric duct and posterior tubules that remain unfused with the duct. In Odd1 mutant mice (+ Wt1 mutants - PMID 9118800) the anterior fused tubules differentiate but the posterior tubules are absent [YAF 23/11/09].

Comments / Discussion points

  • Comparative paper? PMID 19345287 cites mouse, chicken and xenopus orthologs
  • Drosophila use Malpighian tubules for excretion so there is no loop of Henle as such. However there do seem to be common aspects of renal function in flies and vertebrates as indicated in these recent papers:
  • The kidneys of larval and adult amphibians do not develop loops of Henle (LOH). However, the layout of the amphibian pronephros (the fully functional embryonic kidney, which is indispensable for larval life) is very similar to the mammalian adult metanephric kidney, and contains tubules similar to those that make up the LOH of mammals (PMID 17875669). [REF 16/09/09]

1: Singh SR, Hou SX. Multipotent stem cells in the Malpighian tubules of adult Drosophila melanogaster. J Exp Biol. 2009 Feb;212(Pt 3):413-23. Review. PMID 19151216.

2: Weavers H, Prieto-Sánchez S, Grawe F, Garcia-López A, Artero R, Wilsch-Bräuninger M, Ruiz-Gómez M, Skaer H, Denholm B. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature. 2009 Jan 15;457(7227):322-6. Epub 2008 Oct 29. PMID 18971929.

3: Zhuang S, Shao H, Guo F, Trimble R, Pearce E, Abmayr SM. Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development. 2009 Jul;136(14):2335-44. Epub 2009 Jun 10. PMID 19515699.


1. NTR item #2846310: to request a new term 'sodium-dependent L-ascorbic acid transmembrane transporter activity' as mentioned in PMID 10631088 (IDA) for the function of SVCT1/SLC23A1 (Q9UHI7). I'm not sure if it would be a child of either GO:0022857 transmembrane transporter activity or of GO:0008523 sodium-dependent multivitamin transmembrane transporter activity? I also think perhaps that there should be another new term 'L-ascorbic acid transmembrane transporter activity' as a child of GO:0022857 transmembrane transporter activity and GO:0015229 L-ascorbic acid transporter activity and then the term 'sodium-dependent L-ascorbic acid transmembrane transporter activity' could be a child of that (too)? - Midori added: sodium-dependent L-ascorbate transmembrane transporter activity GO:0070890 [YAF 01/09/09]

2. NTR item #2849019: to request new term transepithelial ascorbic acid transport (or transepithelial ascorbate transport) , as a child of GO:0070633 transepithelial transport, for annotation of the SVCT1 and SVCT2 proteins as described in the recent publication PMID 18417304. -Midori added transepithelial L-ascorbic acid transport GO:0070904 [YAF 03/09/09]

For Xenopus irx3 (O42261)

Added SourceForge request: #2859892 for 2 new kidney terms: *SF 2859892: specification of kidney anlage specification of kidney anlage ; GO:NEW, maintenance of kidney anlage identity ; GO:NEW Needed for annotation of PMID 17875669 [REF 16/09/09]

Added SourceForge request: #2860000 for 6 new terms relating to the proximal/distal subdivision of the nephron late in kidney development: *SF 2860000: proximodistal kidney segmentation

    • proximal/distal nephron patterning ; GO:NEW,
    • pronephros proximal/distal patterning ; GO:NEW,
    • specification of nephron tubule identity ; GO:NEW,
    • specification of proximal tubule identity ; GO:NEW,
    • specification of intermediate tubule identity ; GO:NEW,
    • specification of distal tubule identity ; GO:NEW,

[REF 16/09/09]

For Mouse Pou3f3 (Brn1)(P31361)

From PMID 12925600 - IMP studies show that Brn1 is essential for the development and function of the kidney nephron. will need to request new terms (possibly the same as the above 'specification of .....' terms requested by Becky or maybe children of the above? (will need to discuss with Becky)): ie:

    • development(/differentiation/specification) of Loop-of-Henle; GO:NEW, (Fig. 3)
    • development(/differentiation/specification) of distal convoluted tubule; GO:NEW, (Fig 2 and Fig 4)
    • development(/differentiation/specification) of proximal convoluted tubule; GO:NEW, (Fig 2)
    • development(/differentiation/specification) of macula densa; GO:NEW, (Fig 2 and Fig 4)
    • development(/differentiation/specification) of thick ascending limb; GO:NEW, (Fig 2 and Fig 4)
    • development(/differentiation/specification) of thin descending limb; GO:NEW, (Fig. 2)
    • development(/differentiation/specification) of connecting tubule; GO:NEW, (Fig. 2)
    • differentiation of macula densa; GO:NEW, (Fig 4)
    • differentiation of distal convoluted tubule; GO:NEW, (Fig 4)
    • differentiation of thick ascending limb; GO:NEW, (Fig 4)
  • Also Fig.3D (p4755) shows stages in LOH elongation during stages of development. - Anlage (in cortex) -> Primitive loop (in cortex and just entering the medulla) -> Immature loop (throughout medulla reaching to the papilla). [YAF 30/09/09]

For Xenopus irx3 (O42261) and Mouse Pou3f3 (Brn1)(P31361)

    • Expanded the set of new P/D patterning terms I've requested in SF #2860000, to include terms for the macula densa and LOH. [REF 13/10/09]

For P19091 (ANDR_MOUSE)

  • From PMID 11997177 -needed NTR for POU domain binding as a child of GO:0019904 protein domain specific binding.

This is required for annotation of the binding of Androgen receptor protein to the POU domains of Brn1 and Oct1 proteins in PMID 11997177. 'POU domain binding'- GO NEW possible definition: "Interacting selectively and non-covalently with a POU domain of a protein, In eukaryotes, the POU proteins are usually transcription factors" SF#2871338 (YAF 01/10/09). Midori added POU domain binding GO:0070974.

For rat Cited1 (Q4V8P1)

    • requested new term for 'negative regulation of embryonic axis specification' as a child of GO:0000578 embryonic axis specification SF# 2883925 ( for annotation of the rat Cited1 gene, which, when ectopically expressed in Xenopus embryo, blocks axis formation as investigated in PMID 15843474. Response from David Hill said: 'the action of the Cited1 in the experiment that you reference is an example of a dominantgain-of-function experiment. So it is not clear that the Cited1 is playing its normal role. .'
    • requested new term for "metanephric mesenchyme to epithelial transition" as a child of GO:0060231 mesenchymal to epithelial transition which could also be a child of GO:0001656 metanephros development and the new term "negative regulation of metanephric mesenchyme to epithelial transition"(GO NEW) as a child of "metanephric mesenchyme to epithelial transition". SF# 2884040 (; required for annotation of rat cited1 (Q4V8P1) blocking epithelial morphogenesis in metanephric organ culture in PMID 15843474. [YAF 22/10/09]. (David added: metanephros morphogenesis; GO:0003338/ mesenchymal to epithelial transition involved in metanephros morphogenesis; GO:0003337/ regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis; GO:0003339/ negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis; GO:0003340)[YAF 24/11/09]

For mouse Cited1 (P97769)

    • PMID 9811838: requested geneontology-Ontology requests-2893305 NTR: response to interleukin-6/9/11. the following new terms as children of GO:0034097 response to cytokine stimulus: -response to interleukin-6; -response to interleukin-9; -response to interleukin-11[YAF 06/11/09] (Midori added response to interleukin-9 GO:0071104 and response to interleukin-11 GO:0071105 on 09/11/09)[YAF 09/11/09]. PMID 18187554 requested NTR SF#2895106 'response to parathyroid hormone' (as a child of GO:0009725) requested 10/11/09 (Midori added response to parathyroid hormone stimulus GO:0071107).

For Mouse c-myc (P01108)

    • PMID 19161241: requested geneontology-Ontology requests-2893199 NTR +ive regulation of cap mesenchymal cell proliferation as a child of GO:0002053 positive regulation of mesenchymal cell proliferation. [YAF 06/11/09]. David Hill added on 13/11/09: metanephric cap mesenchymal cell proliferation; GO:0090094

regulation of metanephric cap mesenchymal cell proliferation; GO:0090095 positive regulation of metanephric cap mesenchymal cell proliferation; GO:0090096

For Mouse Osr1/Odd1 (Q9WVG7)

requested new terms: SF 2902547 Requested the following new kidney development related terms as indicated. I have tried to fit them into some kind of order by suggesting under which parent term they should be but wasn't too sure.

    • From PMID 16790474 mouse odd1 Q9WVG7 OSR1_MOUSE and Chick Odd1 (no protein/ nucleotide/ IPI entry)

(Osr1-/- deleted mutants used for mouse and chick embryo analysis -IMP).

      • mesenchyme development GO:0060485
      • --<metanephric mesenchyme development GO:NEW
      • mesenchymal cell differentiation GO:0048762
      • --<mesenchymal cell differentiation involved in kidney development GO:NEW
      • --<metanephric mesenchymal cell differentiation GO:NEW
      • to add to Beckys SF #2860000 request for
      • term: specification of nephron tubule identity/differentiation GO:NEW (Becky) (synonym- nephric tubule)
      • -<specification of mesonephric tubule identity/differentiation GO:NEW
      • --<specification of anterior mesonephric tubule identity/differentiation GO:NEW
      • --<specification of posterior mesonephric tubule identity/differentiation GO:NEW
      • tube development GO:0035295
      • --<kidney tubule development GO:NEW
      • --<metanephric tubule formation/development GO:NEW
      • --<mesonephric tubule formation/development GO:NEW
      • epithelial tube morphogenesis GO:0060562
      • --<kidney epithelial tube morphogenesis GO:NEW
      • tube morphogenesis GO:0035239
      • --<nephric duct morphogenesis/formation GO:NEW
      • --<mesonephric duct morphogenesis/formation GO:NEW
      • cell differentiation GO:0030154
      • --<kidney tubule cell differentiation GO:NEW
      • --<regulation of kidney tubule cell differentiation GO:NEW
      • -<negative regulation of kidney tubule cell differentiation GO:NEW
      • kidney precursor cell proliferation GO:NEW.
    • From PMID 18835385 mouse osr1/odd1 Q9WVG7 OSR1_MOUSE

(used temporal fate mapping - Osr+progenitor cells - IMP/IDA?)

      • renal vesicle progenitor cell differentiation GO:NEW
      • vasculature development GO:0001944
      • --<renal vasculature development-GO:NEW
      • mesenchyme development GO:0060485
      • --<cap mesenchyme development/formation/specification GO:NEW
      • --<cortical interstitial mesenchyme development/formation/specification GO:NEW
      • epithelial cell differentiation GO:0030855
      • --<ureteric epithelial cell differentiation GO:NEW
      • smooth muscle cell differentiation GO:0051145
      • --<renal smooth muscle cell differentiation GO:NEW [YAF 23/11/09]

For Mouse Id2 (P41136)

PMID 12456807 - requested new term for "mammary gland alveolar epithelial cell differentiation" SF 2903147 [YAF 24/11/09].

For Mouse Id2 (P41136)

  • Requested the new term: "embryonic endodermal gut morphogenesis" as a child of 'GO:0048558 embryonic gut morphogenesis' to annotate mouse Id2 (P41136) from PMID 16888283; which shows that Id2 is expressed from the period of definitive endoderm before E10.5 and these cells begin to form villi in the small intestine. *SF-SF 2903221: embryonic endodermal gut morphogenesis
  • Requested the new term "Mammary gland alveolus epithelial cell differentiation" as a child of 'GO:0060749 mammary gland alveolus development'; required for annotation of mouse Id2 P41136 in PMID 12456807. *SF-SF 2903147: mammary gland alveolus development [YAF 24-26/11/09]

For Xenopus wt1 (B7ZSG3 and P79958)

Requested new term for glomus development in SF:2903833. Ties in with Yasmin's previous request for a 'renal vasculature development' term (SF:2902547) [REF 24/11/09]

For Mouse Wt1 (P22561)/ Human WT1 (P19544)/ Human BASP1 (P80723) and mouse Basp1 (Q91XV3)

  • To request new term for 'Podocyte differentiation' (IDA)- from PMID 19050011 [YAF 26/11/09]
    • Glomerulus development GO:0032835
      • --<Podocyte development GO:NEW
      • --<Podocyte differentiation GO:NEW (IDA) (NB: this could also be a child of GO:0030855 epithelial cell differentiation)

(Podocytes (or visceral epithelial cells) are cells of the visceral epithelium in the kidneys and form a crucial component of the glomerular filtration barrier, contributing size selectivity and maintaining a massive filtration surface. Adjacent podocytes interdigitate to cover the basal lamina which is intimately associated with the glomerular capillaries, but the podocytes leave gaps or thin filtration slits. The slits are covered by slit diaphragms which are composed of a number of cell-surface proteins including nephrin, podocalyxin, and P-cadherin, which ensure that large macromolecules such as serum albumin and gamma globulin remain in the bloodstream. Small molecules ie: water, glucose, and ionic salts are able to pass through the slit diaphragms and form an ultrafiltrate which is further processed by the nephron to produce urine. Podocytes are also involved in regulation of glomerular filtration rate (GFR). When podocytes contract, they cause closure of filtration slits. This decreases the GFR by reducing the surface area available for filtration) Requested 02/12/09 SF 2907403[YAF 02/12/09].

  • For Human WT1 (P19544) and mouse Wt1 (P22561) PMID 10101119: requested new term 'epicardial (or epicardium) development' as a child of 'GO:0007507 heart development' SF 2908137 [YAF 03/12/09]
  • For mouse Wt1 (P22561) PMID 10077614 will need NTR Mesangium development: updated the following SF request: SF 2905937[YAF 07/12/09]
  • For Human WT1 (P19544) From PMID 8132626, requested the new term "Basal transcription activator activity " as a child of 'GO:0016563 transcription activator activity': SF 2905055 [YAF 27/11/09]

For Rat Egr-1 (PO8154)

To request new terms From PMID 8910451 rat EGR1

    • glomerulus development GO:0032835
      • --<Glomerular mesangium development GO:NEW [Defn The progression of the glomerular mesangium over time from its initial formation until its mature state. The glomerular mesangium is the thin membrane connective tissue composed of mesangial cells, which helps to support the capillary loops in a renal glomerulus].
      • --<Glomerular mesangium cell proliferation GO:NEW (IDA) [Defn: The multiplication or reproduction of glomerular mesangium cells by cell division, resulting in the expansion of their population. Mesangial cells are myofibroblasts phenotypically related to vascular smooth muscle cells, which make up the composition of the glomerular mesangium. The glomerular mesangium is the thin membrane which helps to support the capillary loops in a renal glomerulus] SF 2905937.[YAF 27-30/11/09].
    • NTR "response to heparin" (as a possible child of GO:0009991 response to extracellular stimulus)SF 2905921. [YAF 30/11/09].

From PMID 18723570 New term requested for "(cellular) response to mycophenolic acid" as a child of response to drug GO:0042493 SF 2905973 for rat Egr1 and rat PDGFB (Q05028)[YAF 30/11/09].

For Human BMP4 (P12644)

SF#2907000: requested the new term 'positive regulation of kidney development' GO:NEW as a child of kidney development GO:0001822 (IDA) as investigated in PMID 10021330. Also asked for addition of the term 'Nephrogenesis' to be added as an exact synonym of kidney development SF 2907000. Also need NTR nephric duct morphogenesis which has been requested in SF# 2902547 [YAF 01/12/09].

Kidney Development Review Papers

  • PMID 15554941 Transcriptional control of kidney development. Bouchard M. 2004. Talks about genes involved in nephric lineage specification (Pax2/Pax8/Lim1/Bmp4/Wt1/GDNF1/Eya1/Foxc1); metanephros development - UB positioning, induction, nephron induction, ureter branching, Stromal cell differentiation(Gdnf1/Eya1/Foxc1/2/Slit2/Robo2/Bmp4/Pax2/Hox11(HoxA11/C11/D11)/ Sall1/Wt1/Six1/Wnt4/Emx2/Gata3/BF2/Pod1/Pbx21.
  • PMID 15380247 Recent genetic studies of mouse kidney development. Yu J, McMahon AP, Valerius MT. 2004. Has a nice diagram of the stages of nephron formation on p.551. Also lists genes investigated with particular molecular regulation of outgrowth of the uteric bud and regulation of tubulogenesis (Table 1; p552 - Gdf1, Six1, Slit2/Robo2, Wnt1, Fras1+Grip1, Pod1, Pbx1, Brn1, Psen1/2).
  • PMID 16760375 Role of transcriptional networks in coordinating early events during kidney development. Boyle S, de Caestecker Mark. 2006. Has nice diagrams of stages of early mammalian kidney development. Reviews transcription factors in mesenephric mesenchyme: Eya1/ Foxc1/2/ Hoxa/c/d11/ Pax2/ Pbx1/ Rar-alpha/beta2/ Sall1/ Six1/ Wt1.
  • PMID 12094231 Coordinating early kidney development: lessons from gene targeting. Vainio S, Lin Y. 2002. Nice diagrams of kidney development. List of genes essential for early kidney development (Transcription Factors: Emx2/Eya1/Foxc1/Foxd1/Pax2/Rara,Rarb/Sall1/Wt1; Growth factors: Bmp4/Bmp7/Fgf7/Gdnf/Wnt4; Growth factors/receptors: Gfra1/Notch2/Ret; Proteoglycans and their biosynthetic enzymes: Hs2st/Gpc3.

Kidney Loop of Henle GO Cocuration

Yasmin Alam-Faruque and Emily Dimmer.

  • As the renal community is embracing proteomic technologies at an increasing rate to identify, quantify and characterize a global set of proteins then there is a need to provide a high quality information-rich functional dataset that can be utilized by them to rapidly evaluate new data and generate hypotheses to guide future research seeking to alleviate renal diseases (1).
  • Nephrons are the functional units of the kidney. Each nephron consists of 2 parts: a renal corpuscle where blood plasma is filtered and a renal tubule into which the filtered blood passes. The two components of a renal corpuscle are the glomerulus (capillary network) and the glomerular (Bowman’s) capsule (a double-walled epithelial cup surrounding the glomerular capillaries. Blood plasma is first filtered in the glomerular capsule and then passes into the renal tubule, comprised of 3 main sections: (i) the proximal convoluted tubule, (ii) the loop of Henle (nephron loop) and (iii) distal convoluted tubule. The renal corpuscle and both convoluted tubules lie within the renal cortex whereas the loop of Henle extends into the renal medulla, makes a hairpin turn and then returns to the renal cortex.
  • The main function of the loop of Henle is to create a concentration gradient in the medulla of the kidney and investigators are looking into how the renal concentrating mechanism works in-vivo (2). By means of a mechanism which utilizes sodium pumps, it creates an area of high sodium concentration deep in the medulla, near the collecting duct. Water present in the filtrate in the collecting duct flows through aquaporin channels out of the collecting duct, moving passively down its concentration gradient. This process reabsorbs water and creates a concentrated urine for excretion. The loop of Henle is also involved in reabsorption of filtered Na+, K+, Ca2+, HCO3- Cl- and H2O, and is hence involved in independent regulation of both volume and osmolarity of body fluids. There are various mechanisms in place for this function e.g. For Na+ and Cl-, reabsorption occurs by means of Na+Cl- symporters in the apical membranes; Na+-K+ pumps and Cl- leakage channels in the basolateral menbranes, and the distal convoluted tubule is the major site of parathyroid hormone stimulating reabsorption of Ca2+. There are many genes important for the development and function of the mammalian kidney e.g.: COX-2 has a significant role in the fetal human kidney involved in the development of the nephron (3), and the NADPH oxidases which have a distinct cellular localization in renal vessels including cells of the thick ascending limb of the loop of Henle, may have an important pathophysiological role in regulating angiotensin and salt concentrations (4).
  • The pronephros, mesonephros and metanephros represent three distinct renal organs that function in succession as the vertebrate excretory system during development of the kidney. These three organ systems are derived from intermediate mesoderm and develop according to an ordered temporal process.
  • The loop of Henle structure of the kidney differs considerably between mammals, chicken and frogs. There is a definite loop of Henle structure in the mammalian and avian systems but this physical structure seems to be absent in the frog. However the segment(s) for the area in which the loop of Henle develops is present in Xenopus (Duncan Davidson and Jamie Davies GUDMAP, Personal communication).
  • The renal community consider the Xenopus pronephros as an ideal model for investigating organogenesis and development of renal function in vertebrates (5,6) since Xenopus has been studied and analyzed for many decades and is already a simple and popular animal model for developmental cell biologists.
  • In the avian kidney, 3 types of nephron are identified: mammalian-type nephrons with long and short loops of Henle, and reptilian type nephrons (7).
  • The renal community has also used the chicken in their studies investigating amino acid transport process across cell membranes (8).
Work Plan
  • From speaking with renal researchers at GUDMAP, the loop of Henle structure was thought to be an interesting subject – as the structure is known to change rapidly been different organisms (see above). Therefore it would be interesting to see how functions of gene products in mammalian, avian and amphibian species change during the evolution of the loop of Henle structure.
  • We thought that perhaps a concurrent GO annotation exercise by curators on orthologous genes in the human/mouse, chicken and Xenopus species might result in quite a nice publication. The loop of Henle might be an ideal focus as there would be enough genes to create a large-enough annotation set to be able to analyse well, yet not too many for us to be overwhelmed by the amount of effort required for such a project!
  • Individual studies on the functional specialization of orthologous genes in distinct species has been carried out for single genes (e.g. the Na-K-Cl cotransporter); (9), and also papers describing the comparative anatomy of different loop of Henle structures (10), however this project will enable a wide review of the functional information available for orthologs of genes in different species.
  • Such a target list could be obtained from looking at GUDMAP gene expression database, which provides those genes shown to be specifically expressed in the murine loop of Henle; .
  • From a list of 155 mouse genes expressed in the loop of Henle, 126 Ensembl identifiers for orthologues in Xenopus tropicalis, 65 UniProtKB accessions obtained for chicken (Gallus gallus), 83 UniProtKB accessions for human and 84 UniProtKB accessions for rat have been located from initial searches using Clustr and Ensembl BioMart. It is likely additional orthologs will be located during the project for these organisms, and additional genes known to be important in the Loop of Henle would supplement this list during the project (11).
  • A quick review of the first 15 in this list, using the NCBI PubMed resource, found that 13 of the 15 appear to have some known kidney-related function (indicating that the method used to generate the list appears viable), that human/mouse have publications for all of selected genes, whereas the chicken ortholog have publications for 13, and Xenopus for 11 of the selected 15 genes; indicating that there appears to be enough literature to support this curation effort in each of the three species.
  • Curators will be asked to annotate a maximum of 200 proteins, with those genes that over-lap with those targeted by the AgBase team prioritized.
  • It is envisaged that this project will take around 8-12 months to complete since it will not be worked on full-time by the Xenopus and chicken curators, and will need to fit in with the priorities of these different groups. Progress will be monitored and reported to the groups involved at quarterly intervals. A central document page will be developed by Yasmin (probably using a GO wiki) which will be accessible by all concerned. This page will act as a central resource for the project and list all the genes names and corresponding accessions for each organism that will be targeted by this project. This will help in monitoring the progress of this project, highlight interesting points/difficulties, supported by email communication between all the curators involved.
  • The annotations will be analyzed at the end of the project, to highlight the most frequent reasons for the functional differences between species – such as lack/addition of specific splice variants, with unique functional characteristics between the species. Changes will also be displayed visually n GO slim views compare each of the proteomes.
  • Contacts with kidney experts will be made for each of the three species, to seek additional value for the project.
  • The benefits in this project include:
    • focused development of GO terms to more accurately describe renal-associated processes
    • instigate contacts with renal groups who might be interested in contributing to this project
    • UniProtKB will receive feedback where information is available for improvement of Swiss-Prot entries.
    • generation of a publication which will:
      • highlight not only biological insights into the similarities and differences of the orthologous genes in these distinct species
      • demonstrate the usefulness of focused, collaborative cross-species GO annotation
      • demonstrate to users the usefulness of functional annotation associated with specific UniProtKB accessions
      • provide publicity for the UniProtKB, AgBase and GOA resources.
      • publicity for the Renal annotation initiative; encourage feedback and possible future collaborations.

1. Janech, MG, Raymond JR, Arthur JM (2007); Proteomics in renal research; Am J Pysiol Renal Physiol; 292(2), F501-12 (PMID 17107941).

2. Halperin ML, Kamel KS, Oh MS (2008), Mechanisms to concentrate the urine: an opinion. Curr Opin Nephrol Hypertens; 17(4), 416-22 (PMID 18660679).

3. Khan KN, Stanfield KM et al; (2001); Cylooxygenase-2-expression in the developing human kidney Pediatr Dev Path 4(4) 461-6 (PMID 11779048).

4. Chan T, Asashima M (2006) Growing kidney in the Frog; Nephron Exp Nephrol; 103, e81-85 (PMID 16554664).

5. Gill PS, Wilcox CS (2006); NADPH oxidases in the kidney; Antioxid Redox Signal 8(9-10), 1597-607 (PMID 16987014).

6. Jones EA (2005); Xenopus: a prince among models for pronephric kidney development; J Am Soc Nephrol 16(2), 313-21 (PMID 15647339).

7. Gambaryan SP (1992); Development of the metanephros in the chick: maturation of glomerular size and nephron length; Anat Embryol (Berl); 185(3):291-7. (PMID 1575329).

8. Lerner J (1984) Cell membrane amino acid transport processes in the domestic fowl (Gallus domesticus). Comp Biochem Physiol A Comp Physiol; 78(2):205-15. (PMID 6146442).

9. Gagnon E, Forbush B, Caron L, Isenring P.(2003) Functional comparison of renal Na-K-Cl cotransporters between distant species. Am J Physiol Cell Physiol.284(2):C365-70. (PMID 12388059).

10. Bankir, L., and de Rouffignac, C. (1985) Urinary concentrating ability : insights from comparative anatomy. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 249: p.643-666. (PMID 3934988)

11. Dihazi H., Rahman, AA., Agarwal, NK, Doncheva, Y., Muller, GA. (2005) Proteomics analysis of cellular response to osmotic stress in TALH-cells. Mol. Cell Proteomics 4: 1445-1458.(PMID 15975915)

[[Link title]] Yasmin Alam-Faruque 13:27, 18 August 2009 (UTC)