RRC ID 82471
Author Omata K, Kashima M, Ohkido-Yamamoto M, Murai N, Ishikawa K, Hirata H, Kato T.
Title Canonical and Non-Canonical Functions of Erythropoietin and Its Receptor in Mature Nucleated Erythrocytes of Western Clawed Frog, Xenopus tropicalis.
Journal Zoolog Sci
Abstract Enucleated erythrocytes are characteristic of adult mammals. In contrast, fish, amphibians, reptiles, birds, and fetal mammals possess nucleated erythrocytes in their circulation. Erythroid maturation is regulated by erythropoietin (EPO) and its receptor (EPOR), which are conserved among vertebrates. In mammals, EPOR on the erythroid progenitor membrane disappears after terminal differentiation. However, in western clawed frog, Xenopus tropicalis, mature erythrocytes maintain EPOR expression, suggesting that they have non-canonical functions of the EPO-EPOR axis rather than proliferation and differentiation. In this study, we investigated the non-canonical functions of EPOR in Xenopus mature erythrocytes. EPO stimulation of peripheral erythrocytes did not induce proliferation but induced phosphorylation of intracellular proteins, including signal transducer and activator of transcription 5 (STAT5). RNA-Seq analysis of EPO-stimulated peripheral erythrocytes identified 45 differentially expressed genes (DEGs), including cytokine inducible SH2 containing protein gene (cish) and suppressor of cytokine signaling 3 gene (socs3), negative regulators of the EPOR-Janus kinase (JAK)-STAT pathway. These phosphorylation studies and pathway analysis demonstrated the activation of the JAK-STAT pathway through EPO-EPOR signaling in erythrocytes. Through comparison with EPO-responsive genes in mouse erythroid progenitors obtained from a public database, we identified 31 novel EPO-responsive genes indicating non-canonical functions. Among these, we focused on ornithine decarboxylase 1 gene (odc1), which is the rate-limiting enzyme in polyamine synthesis and affects hematopoietic progenitor differentiation and the endothelial cell response to hypoxic stress. An EPO-supplemented culture of erythrocytes showed increased odc1 expression followed by a decrease in polyamine-rich erythrocytes, suggesting EPO-responsive polyamine excretion. These findings will advance our knowledge of the unknown regulatory systems under the EPO-EPOR axis and functional differences between vertebrates' nucleated and enucleated erythrocytes.
Volume 41(4)
Pages 329-341
Published 2024-8-1
DOI 10.2108/zs240004
PMID 39093279
MeSH Animals Erythroblasts / metabolism Erythrocytes* / metabolism Erythropoietin* / genetics Erythropoietin* / metabolism Gene Expression Regulation Receptors, Erythropoietin* / genetics Receptors, Erythropoietin* / metabolism Signal Transduction Xenopus*
Resource
Clawed frogs / Newts Xenopus tropicalis