Alternative titles; symbols
HGNC Approved Gene Symbol: APELA
Cytogenetic location: 4q32.3 Genomic coordinates (GRCh38) : 4:164,877,178-164,899,007 (from NCBI)
ELA encodes a conserved hormone that is critical for heart morphogenesis and signals through the apelin receptor (APLNR; 600052) (Chng et al., 2013).
Chng et al. (2013) isolated a gene, formerly annotated as a noncoding transcript (GenBank AK092578), predicted to encode an evolutionarily conserved 54-amino acid protein with a 22-residue N-terminal signal peptide. The processed 32-amino acid (4 kD) peptide, designated ELA, was detected following microinjection of the human mRNA into Xenopus oocytes. The authors speculated that this secreted hormone may have evaded discovery by protein prediction algorithms because of the small size of the open reading frame. ELA is most highly expressed in undifferentiated human embryonic stem cells and is rapidly downregulated during differentiation. It is localized in the Golgi apparatus.
Chng et al. (2013) stated that the ELA gene contains 3 exons.
Chng et al. (2013) stated that the ELA gene maps to chromosome 4.
Gross (2014) mapped the ELA gene to chromosome 4q32.3 based on an alignment of the ELA sequence (GenBank AK092578) with the genomic sequence (GRCh37).
Chng et al. (2013) determined that Ela is expressed in zebrafish embryonic ectodermal cells. Knockout of Ela caused zebrafish embryos to develop with a rudimentary heart or no heart at all, which phenocopied the loss of Aplnr. Overexpression of zebrafish or human APLNR in HEK293 cells was sufficient to confer cell surface binding of zebrafish Ela conjugated to alkaline phosphatase (see 171760), indicating that APLNR is the cognate receptor for ELA.
Using RNA in situ hybridization, mass spectrometry, and GFP fusion proteins, Pauli et al. (2014) analyzed the expression, production, and secretion, respectively, of a signaling protein that they called Toddler, also known as Apela/Elabela/Ende. Pauli et al. (2014) used transcription activator-like effector (TALE) nucleases to generate frameshift mutations in the Toddler gene. To complement loss-of-function analyses with gain-of-function studies, Toddler was misexpressed through mRNA or peptide injection. Toddler mutants were rescued through global or localized Toddler production. The relationship between Toddler and APJ/apelin receptors was studied through genetic interaction and receptor internalization experiments. Loss or overproduction of Toddler reduced cell movements during zebrafish gastrulation; mesodermal and endodermal cells were slow to internalize and migrate. Both the local and ubiquitous expression of Toddler were able to rescue gastrulation movements in Toddler mutants, suggesting that Toddler acts as a motogen, a signal that promotes cell migration. Toddler activates G protein-coupled APJ/apelin receptor signaling, as evidenced by Toddler-induced internalization of APJ/apelin receptors and rescue of Toddler mutants through expression of the known receptor agonist apelin (300297). Pauli et al. (2014) concluded that their findings indicated that Toddler promotes cell movement during zebrafish gastrulation by activation of APJ/apelin receptor signaling and that Toddler does not seem to act as a chemoattractant or -repellent, but rather as a global, signal that promotes the movement of mesendodermal cells. Since both loss and overproduction of Toddler reduce cell movement, Toddler levels need to be tightly regulated during gastrulation.
Ho et al. (2017) showed that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR), is a circulating hormone secreted by the placenta. Elabela but not Apelin knockout pregnant mice exhibited preeclampsia-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. In mice, infusion of exogenous ELA normalized hypertension, proteinuria, and birth weight. ELA, which is abundant in human placentas, increased the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent preeclampsia. Zygotic deletion of ELA in the mouse caused midgestation lethality due to cardiovascular defects and phenocopied loss of APLNR.
Chng, S. C., Ho, L., Tian, J., Reversade, B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev. Cell 27: 672-680, 2013. [PubMed: 24316148] [Full Text: https://doi.org/10.1016/j.devcel.2013.11.002]
Gross, M. B. Personal Communication. Baltimore, Md. 1/13/2014.
Ho, L., van Dijk, M., Chye, S. T. J., Messerschmidt, D. M., Chng, S. C., Ong, S., Yi, L. K., Boussata, S., Goh, G. H.-Y., Afink, G. B., Lim, C. Y., Dunn, N. R., Solter, D., Knowles, B. B., Reversade, B. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science 357: 707-713, 2017. [PubMed: 28663440] [Full Text: https://doi.org/10.1126/science.aam6607]
Pauli, A., Norris, M. L., Valen, E., Chew, G.-L., Gagnon, J. A., Zimmerman, S., Mitchell, A., Ma, J., Dubrulle, J., Reyon, D., Tsai, S. Q., Joung, J. K., Saghatelian, A., Schier, A. F. Toddler: an embryonic signal that promotes cell movement via apelin receptors. Science 343: 1248636, 2014. Note: Electronic Article. [PubMed: 24407481] [Full Text: https://doi.org/10.1126/science.1248636]