Erythropoietin Gene Expression: Developmental-Stage Specificity, Cell-Type Specificity, and Hypoxia Inducibility

Invited Review

Erythropoietin Gene Expression: Developmental-Stage Specificity, Cell-Type Specificity, and Hypoxia Inducibility

NORIO SUZUKI¹

¹Division of Interdisciplinary Medical Science, Center for Oxygen Medicine, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

Erythrocytes play an essential role in the delivery of oxygen from the lung to every organ; a decrease in erythrocytes (anemia) causes hypoxic stress and tissue damage. To maintain oxygen homeostasis in adult mammals, when the kidney senses hypoxia, it secretes an erythroid growth factor, erythropoietin (Epo), which stimulates erythropoiesis in the bone marrow. Recently, studies using genetically modified mice have shown that the in vivo expression profile of the Epo gene changes dramatically during development. The first Epo-producing cells emerge in the neural crest and neuroepithelium of mid-stage embryos and support primitive erythropoiesis in the yolk sac. Subsequently, Epo from the hepatocytes stimulates erythropoiesis in the fetal liver of later stage embryos in a paracrine manner. In fact, erythroid lineage cells comprise the largest cell population in the fetal liver, and hepatocytes are distributed among the erythroid cell clusters. Adult erythropoiesis in the bone marrow requires Epo that is secreted by renal Epo-producing cells (REP cells). REP cells are widely distributed in the renal cortex and outer medulla. Hypoxia-inducible Epo production both in hepatocytes and REP cells is controlled at the gene transcription level that is mainly mediated by the hypoxia-inducible transcription factor (HIF) pathway. These mouse studies further provide insights into the molecular mechanisms of the cell-type specific, hypoxia-inducible expression of the Epo gene, which involves multiple sets of cis- and trans-regulatory elements.

keywords —— anemia; erythropoiesis; genetically modified mouse; renal erythropoietin-producing cell; transcriptional regulation

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Tohoku J. Exp. Med., 2015, 235, 233-240

Correspondence: Norio Suzuki, Division of Interdisciplinary Medical Science, Center for Oxygen Medicine, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

e-mail: sunorio@med.tohoku.ac.jp