ELA_MOUSE
ID ELA_MOUSE Reviewed; 54 AA.
AC P0DMC4;
DT 19-FEB-2014, integrated into UniProtKB/Swiss-Prot.
DT 19-FEB-2014, sequence version 1.
DT 03-AUG-2022, entry version 44.
DE RecName: Full=Apelin receptor early endogenous ligand {ECO:0000312|MGI:MGI:3642370};
DE AltName: Full=Protein Elabela {ECO:0000250|UniProtKB:P0DMC2};
DE Short=ELA {ECO:0000250|UniProtKB:P0DMC2};
DE AltName: Full=Protein Toddler {ECO:0000250|UniProtKB:P0DMC2};
DE Flags: Precursor;
GN Name=Apela {ECO:0000312|MGI:MGI:3642370}; Synonyms=Ela, Ende, Gm10664, Tdl;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Marra M., Hillier L., Kucaba T., Martin J., Beck C., Wylie T.,
RA Underwood K., Steptoe M., Theising B., Allen M., Bowers Y., Person B.,
RA Swaller T., Gibbons M., Pape D., Harvey N., Schurk R., Ritter E., Kohn S.,
RA Shin T., Jackson Y., Cardenas M., McCann R., Waterston R., Wilson R.;
RT "The WashU-NCI mouse EST project 1999.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=20153842; DOI=10.1016/j.gep.2010.02.001;
RA Hassan A.S., Hou J., Wei W., Hoodless P.A.;
RT "Expression of two novel transcripts in the mouse definitive endoderm.";
RL Gene Expr. Patterns 10:127-134(2010).
RN [5]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=26611206; DOI=10.1007/s00395-015-0521-6;
RA Perjes A., Kilpioe T., Ulvila J., Magga J., Alakoski T., Szabo Z.,
RA Vainio L., Halmetoja E., Vuolteenaho O., Petaejae-Repo U., Szokodi I.,
RA Kerkelae R.;
RT "Characterization of apela, a novel endogenous ligand of apelin receptor,
RT in the adult heart.";
RL Basic Res. Cardiol. 111:2-2(2016).
RN [6]
RP FUNCTION.
RX PubMed=28371822; DOI=10.1093/cvr/cvx061;
RA Sato T., Sato C., Kadowaki A., Watanabe H., Ho L., Ishida J., Yamaguchi T.,
RA Kimura A., Fukamizu A., Penninger J.M., Reversade B., Ito H., Imai Y.,
RA Kuba K.;
RT "ELABELA-APJ axis protects from pressure overload heart failure and
RT angiotensin II-induced cardiac damage.";
RL Cardiovasc. Res. 113:760-769(2017).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=28854362; DOI=10.1016/j.celrep.2017.08.014;
RA Freyer L., Hsu C.W., Nowotschin S., Pauli A., Ishida J., Kuba K.,
RA Fukamizu A., Schier A.F., Hoodless P.A., Dickinson M.E.,
RA Hadjantonakis A.K.;
RT "Loss of Apela peptide in mice causes low penetrance embryonic lethality
RT and defects in early mesodermal derivatives.";
RL Cell Rep. 20:2116-2130(2017).
RN [8]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=28890073; DOI=10.1016/j.devcel.2017.08.008;
RA Sharma B., Ho L., Ford G.H., Chen H.I., Goldstone A.B., Woo Y.J.,
RA Quertermous T., Reversade B., Red-Horse K.;
RT "Alternative progenitor cells compensate to rebuild the coronary
RT vasculature in Elabela- and Apj-deficient hearts.";
RL Dev. Cell 42:655-666(2017).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE,
RP AND DISRUPTION PHENOTYPE.
RX PubMed=28663440; DOI=10.1126/science.aam6607;
RA Ho L., van Dijk M., Chye S.T.J., Messerschmidt D.M., Chng S.C., Ong S.,
RA Yi L.K., Boussata S., Goh G.H., Afink G.B., Lim C.Y., Dunn N.R., Solter D.,
RA Knowles B.B., Reversade B.;
RT "ELABELA deficiency promotes preeclampsia and cardiovascular malformations
RT in mice.";
RL Science 357:707-713(2017).
CC -!- FUNCTION: Endogenous ligand for the apelin receptor (APLNR) (By
CC similarity). Hormone required for mesendodermal differentiation, blood
CC vessels formation and heart morphogenesis during early development and
CC for adult cardiovascular homeostasis (PubMed:28371822, PubMed:28854362,
CC PubMed:28890073, PubMed:28663440). Drives internalization of the APLNR
CC (By similarity). Acts as a motogen by promoting mesendodermal cell
CC migration during gastrulation by binding and activating APLNR (By
CC similarity). Acts as an early embryonic regulator of cellular movement
CC with a role in migration and development of cardiac progenitor cells
CC (PubMed:28854362). May act as a chemoattractant for the activation of
CC angioblast migration toward the embryonic midline, i.e. the position of
CC the future vessel formation, during vasculogenesis (By similarity).
CC Positively regulates sinus venosus (SV)-derived endothelial cells
CC migration into the developing heart to promote coronary blood vessel
CC sprouting (PubMed:28890073). Plays a role in placental vascular
CC development; promotes placental trophoblast invasion and spiral artery
CC remodeling in the uterus (PubMed:28663440). Involved in the regulation
CC of maternal cardiovascular homeostasis to prevent gestational
CC hypertension and for potent cardioprotective functions during heart
CC failure (PubMed:28371822, PubMed:28663440). Mediates myocardial
CC contractility in an ERK1/2-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:P0DMC2, ECO:0000250|UniProtKB:P0DMC3,
CC ECO:0000250|UniProtKB:P0DP76, ECO:0000269|PubMed:28371822,
CC ECO:0000269|PubMed:28663440, ECO:0000269|PubMed:28854362,
CC ECO:0000269|PubMed:28890073}.
CC -!- SUBUNIT: Interacts with APLNR. {ECO:0000250|UniProtKB:P0DMC3}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:28663440}. Secreted,
CC extracellular space {ECO:0000269|PubMed:28663440}. Note=Found in blood
CC plasma (By similarity). Found in serum of pregnant mice, peaking at
CC midgestation; indicating a maternal and zygotic origin of circulating
CC APELA during pregnancy (PubMed:28663440).
CC {ECO:0000250|UniProtKB:P0DMC3, ECO:0000269|PubMed:28663440}.
CC -!- TISSUE SPECIFICITY: Expressed in the placenta (PubMed:28663440).
CC Expressed in syncytiotrophoblasts of the placenta labyrinth at 10.5 dpc
CC (PubMed:28663440). Expressed in placental chorionic trophoblasts (at
CC protein level) (PubMed:28663440). Expressed in a small population of
CC epiblast cells in the distal half of the embryo at 7 dpc
CC (PubMed:20153842, PubMed:28854362). Expressed in newly formed
CC definitive endoderm cells in the proximal half of the embryo, while it
CC is not present in extra-embryonic endoderm at 7.5 dpc (PubMed:20153842,
CC PubMed:28854362). This expression pattern then changes to the ventral
CC aspect of the developing foregut pocket and the entire hindgut pocket
CC at 8.5 dpc, before becoming restricted to the foregut overlying the
CC heart and the posterior-most hindgut (PubMed:20153842). Not detected in
CC endothelial precursor cells of the yolk sac at 8 dpc (PubMed:28663440).
CC Expressed in extraembryonic tissues as well as in the chorion at 8.25
CC dpc (PubMed:28854362). Expressed in endometrial stroma of the uterus of
CC pregnant mice at 8.5 dpc (PubMed:28663440). Expressed in the developing
CC heart, caudal neural tube and trophobasts at 9 dpc (PubMed:28663440).
CC Expressed in the chorionic plate of the chorioallantoic placenta at 9
CC dpc (PubMed:28663440). Expressed in the posterior half of the ventral
CC neural tube at 9.25 dpc (PubMed:20153842). Expressed in trophoblast
CC cells at the periphery of the placenta at 9.5 dpc (PubMed:28854362).
CC Expressed in collecting ducts of the kidney of pregnant mice at 10.5
CC dpc (PubMed:28663440). Expressed in the epicardium of the developing
CC heart at 11.5 dpc (PubMed:26611206, PubMed:28890073). Expressed weakly
CC in the adult heart (PubMed:26611206). Expressed in endothelial cells
CC and fibroblasts and weakly in cardiomyocytes (PubMed:26611206).
CC {ECO:0000269|PubMed:20153842, ECO:0000269|PubMed:26611206,
CC ECO:0000269|PubMed:28663440, ECO:0000269|PubMed:28854362,
CC ECO:0000269|PubMed:28890073}.
CC -!- DEVELOPMENTAL STAGE: Expressed during early embryonic development from
CC the two cell to blastocyst stages (PubMed:28663440). Expressed in
CC populations of the definitive endoderm from 7 to 8.5 dpc
CC (PubMed:20153842). {ECO:0000269|PubMed:20153842,
CC ECO:0000269|PubMed:28663440}.
CC -!- INDUCTION: Up-regulated following myocardial infarction (MI) (at
CC protein level) (PubMed:26611206). {ECO:0000269|PubMed:26611206}.
CC -!- DISRUPTION PHENOTYPE: Mice lacking APELA are not represented at the
CC expected Mendelian ratios (PubMed:28854362, PubMed:28663440). Mutant
CC embryos exhibit around 10% to 50% incidence of incomplete penetrance of
CC embryonic lethality (PubMed:28854362, PubMed:28663440). Fetal death is
CC increased especially in mothers devoid of all Apela expression
CC (PubMed:28663440). Mutant embryos show extraembryonic tissues
CC anomalies, such as ectopic anterior chorion, mesoderm yolk sac and
CC blood island protrusions and reduced allantois thickness at 8.25 dpc
CC (PubMed:28854362). Mutant embryos show improper establishment of the
CC fetal-maternal circulation, such as underdeveloped yolk sac
CC vasculature, embryonic vascular malformations and impaired cardiac tube
CC looping at 9.5 and 10.5 dpc (PubMed:28854362, PubMed:28663440). Show
CC also defect in somitic vasculature at 10.5 dpc. The heart of mutant
CC embryos show reduced coronary vessel growth at 13.5 dpc and 15.5 dpc
CC (PubMed:28890073). The placenta of mutant pregnant mice show decreased
CC labyrinth thickness, poor vasculature and decreased cell proliferation
CC (PubMed:28663440). Mutant pregnant mice that survived to adulthood
CC developed preeclampsia, including increased systolic blood pressure,
CC proteinuria, and glomerular endotheliosis (PubMed:28663440). Mutant
CC embryos show altered expression of several erythroid and myeloid
CC progenitor genes at 7.5 dpc (PubMed:28854362). Mutant embryos show
CC increased expression of hypoxia-related genes in the placenta at 10.5
CC (PubMed:28663440). Double knockout mice of APELA and APLN genes exhibit
CC the same penetrance, embryonic lethality and cardiovascular
CC malformations as single APELA knockout mice (PubMed:28854362).
CC {ECO:0000269|PubMed:28663440, ECO:0000269|PubMed:28854362,
CC ECO:0000269|PubMed:28890073}.
CC -!- SIMILARITY: Belongs to the Elabela/Toddler family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AK014119; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK014119; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AI930099; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; GL456145; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS80883.1; -.
DR RefSeq; NP_001284483.1; NM_001297554.1.
DR RefSeq; XP_011240549.1; XM_011242247.2.
DR AlphaFoldDB; P0DMC4; -.
DR SMR; P0DMC4; -.
DR STRING; 10090.ENSMUSP00000140510; -.
DR PRIDE; P0DMC4; -.
DR Ensembl; ENSMUST00000124790; ENSMUSP00000139425; ENSMUSG00000079042.
DR Ensembl; ENSMUST00000142822; ENSMUSP00000140510; ENSMUSG00000079042.
DR GeneID; 100038489; -.
DR KEGG; mmu:100038489; -.
DR UCSC; uc009lvh.3; mouse.
DR CTD; 100506013; -.
DR MGI; MGI:3642370; Apela.
DR VEuPathDB; HostDB:ENSMUSG00000079042; -.
DR eggNOG; ENOG502TDEQ; Eukaryota.
DR GeneTree; ENSGT00950000183499; -.
DR HOGENOM; CLU_3049692_0_0_1; -.
DR OMA; GCSHRRC; -.
DR OrthoDB; 1635238at2759; -.
DR BioGRID-ORCS; 100038489; 0 hits in 32 CRISPR screens.
DR PRO; PR:P0DMC4; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; P0DMC4; protein.
DR Bgee; ENSMUSG00000079042; Expressed in renal medulla collecting duct and 63 other tissues.
DR Genevisible; P0DMC4; MM.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0031704; F:apelin receptor binding; ISS:UniProtKB.
DR GO; GO:0005179; F:hormone activity; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0060183; P:apelin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0090134; P:cell migration involved in mesendoderm migration; ISS:UniProtKB.
DR GO; GO:0060976; P:coronary vasculature development; IMP:UniProtKB.
DR GO; GO:0035050; P:embryonic heart tube development; IMP:UniProtKB.
DR GO; GO:0007492; P:endoderm development; ISS:UniProtKB.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0090133; P:mesendoderm migration; ISS:UniProtKB.
DR GO; GO:0007509; P:mesoderm migration involved in gastrulation; ISS:UniProtKB.
DR GO; GO:0060674; P:placenta blood vessel development; IMP:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:1903589; P:positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:1904022; P:positive regulation of G protein-coupled receptor internalization; ISO:MGI.
DR GO; GO:0045823; P:positive regulation of heart contraction; ISS:UniProtKB.
DR GO; GO:1901165; P:positive regulation of trophoblast cell migration; ISS:UniProtKB.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:MGI.
DR GO; GO:0001570; P:vasculogenesis; IMP:UniProtKB.
PE 1: Evidence at protein level;
KW Angiogenesis; Developmental protein; Differentiation; Gastrulation;
KW Hormone; Reference proteome; Secreted; Signal.
FT SIGNAL 1..23
FT /evidence="ECO:0000250|UniProtKB:P0DMC3"
FT CHAIN 24..54
FT /note="Apelin receptor early endogenous ligand"
FT /id="PRO_0000425558"
FT CONFLICT 23
FT /note="Q -> H (in Ref. 2; AI930099)"
FT /evidence="ECO:0000305"
FT CONFLICT 26
FT /note="V -> D (in Ref. 2; AI930099)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 54 AA; 6828 MW; A1EE6D4312683346 CRC64;
MRFQPLFWVF FIFAMSLLFI SEQKPVNFPR RRKLYRHNCF RRRCIPLHSR VPFP
