ELABELA: a novel hormone in cardiac development acting as a new endogenous ligand for the APJ receptor.

Human ELA consists of three exons on chromosome 4, which generates a transcript (AK092578) that is annotated as a non-coding RNA. However, Chng et al. [1] has found that this gene contains a conserved open reading frame predicted to express a conserved vertebrate protein of 54 amino acids (aa) consisting of a secretory signal and a mature 32-aa peptide, which was called as ELABELA (ELA). The sequence of human mature ELA is Gln-Arg-Pro-Val-AsnLeu-Thr-Met-Arg-Arg-Lys-Leu-Arg-Lys-His-Asn-Cys-LeuGln-Arg-Arg-Cys-Met-Pro-Leu-His-Ser-Arg-Val-Pro-Phe-Pro. Phylogenetic analysis revealed that the 32-aa mature peptide is evolutionarily highly conserved, with the last 13 residues being nearly invariant in all vertebrate species. ELA has also been previously reported to be highly expressed in undifferentiated human embryonic stem cells (hESCs) and be sharply down-regulated during differentiation [2]. Chng et al. [1] used an allelic series of zebrafish ELA mutants to show that ELA deficiency leads to severe defects in cardiac morphogenesis and often results in the complete absence of a heart. ELA mutant displayed specific defects in the mesendodermal lineage during gastrulation, as observed by the reduction of gata5 and sox17 expression. Taking together, these results suggested that ELA plays a role in the regulation of heart development. Whereas till now, no hormonal peptides has been reported to be involved in early development, particularly in the formation of the three embryonic germ layers. Chng et al. [1] first discovered an endogenous peptide hormone with potent embryonic signaling activity, which has great prospects in therapeutic applications such as heart repair and gene therapy in development. During embryogenesis, six key signaling pathways (Wnt [3], Bmp/Nodal [4], FGF/IGF [5], Notch [6], Hedgehog [7], and Hippo [8]) have been reported to be crucial for embryonic patterning. Chng et al. [1] tried to explain ELA’s functions in cardiac development by activating APJ receptor. Their reasons are as follows: i) ELA is concomitantly expressed with APJ (APLNR) before the onset of gastrulation. ii) The phenotypes of zebrafish ELA mutants stingingly resemble those of the APJ (APLNR) mutants specifically in cardiogenesis. iii) Extracellular ELA binds to APJ in a native cellular context. To our knowledge, APJ is a G protein-coupled receptor and its endogenous ligand is apelin. Apelin activates APJ receptor, and plays an important role in the physiological activities [9–11], especially in cardiovascular system [12]. However, a recent report has shown that APJ has some functions independent of apelin. Moreover, except apelin, APJ has also been activated by stretch in cardiac hypertrophy [13]. Researchers have tried to explore a second ligand for APJ. Chng et al. [1] stated that ELA, not apelin, is hence the long-sought-after alternative and earlier ligand for APJ, functioning in early cardiovascular development [1]. They demonstrated that the expression of ELA happens earlier than apelin and is concomitantly with APJ before the onset of gastrulation. Then, APJ depletion has different effects on cardiac morphogenesis compared with the depletion of apelin in zebrafish [14,15], frog embryos [15], and mice [16,17]. Whereas loss of ELA phenocopies the loss of APLNR (APJ gene). Based on these, they declared that ELA may be the second ligand for APJ in mediating endoderm differentiation and subsequent cardiogenesis. They first confirmed that a second ligand of APJ really exists in vivo, which forms another essential signaling axis in heart development. A further study supported this claim by reporting that a secreted peptide Toddler activates APJ signaling to promote the subsequent zebrafish gastrulation movements [18]. As we all know, apelin activated APJ signals through Gai by increasing the content of phosphorylated extracellular signal-regulated kinase (p-ERK). It was also reported that stretch may activate APJ receptor by recruiting b-arrestin. However, how ELA activates APJ in vivo is still unclear. ELA acts as an endogenous secreted peptide like apelin. It may have the same pathway as apelin in the activation of APJ. But more studies are needed. No matter what the signal will be, ELA’s function in cardiac development suggested that the ELA/APJ axis appears to be exclusive for endoderm development. Therefore, it opens a new field for future research. Acta Biochim Biophys Sin 2014, 46: 620–622 |a The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmu032. Advance Access Publication 14 May 2014