Abstract
Erythropoietin (Epo) and its receptor (EpoR) are required for the regulation of erythropoiesis. Epo binds to the EpoR homodimer on the surface of erythroid progenitors and erythroblasts, and positions the intracellular domains of the homodimer to be in close proximity with each other. This conformational change is sufficient for the initiation of Epo-EpoR signal transduction. Here, we established a system of chemically regulated erythropoiesis in transgenic mice expressing a modified EpoR intracellular domain (amino acids 247–406) in which dimerization is induced using a specific compound (chemical inducer of dimerization, CID). Erythropoiesis is reversibly induced by oral administration of the CID to the transgenic mice. Because transgene expression is limited to hematopoietic cells by the Gata1 gene regulatory region, the effect of the CID is limited to erythropoiesis without adverse effects. Additionally, we show that the 160 amino acid sequence is the minimal essential domain of EpoR for intracellular signaling of chemically inducible erythropoiesis in vivo. We propose that the CID-dependent dimerization system combined with the EpoR intracellular domain and the Gata1 gene regulatory region generates a novel peroral strategy for the treatment of anemia.
Highlights
Erythropoietin (Epo) is a 34-kDa glycoprotein that interacts with its specific receptor (EpoR) to regulate growth, differentiation, and survival of erythroid progenitors in response to reduced oxygen delivery [1, 2]
Using the chemically inducible homodimer system, we first generated a transgene expressing idEpoRic, which consists of a myristoylation signal peptide, 2 chemical inducer of dimerization (CID)-binding proteins (DmrB), the mouse EpoR intracellular subdomain, and GFP (Fig. 1A) under the control of G1HRD, which allows expression in erythroid cells [21, 25]
We established a transgenic mouse model in which erythropoiesis was reversibly controlled by the administration of a small molecule CID, which induced the dimerization of a 160 amino acid sequence derived from the EpoR intracellular domain
Summary
Erythropoietin (Epo) is a 34-kDa glycoprotein that interacts with its specific receptor (EpoR) to regulate growth, differentiation, and survival of erythroid progenitors in response to reduced oxygen delivery [1, 2]. Epo is produced mainly by renal Epo-producing cells (REP cells) in the kidney in a hypoxia-inducible manner, and its production is reduced in patients with chronic kidney disease [3,4,5,6]. Recombinant human erythropoietin (rHuEPO) is widely used to correct anemia associated with Epo deficiency. RHuEPO administration alleviates the necessity for blood transfusions and greatly improves patient quality of life [1]. High doses of rHuEPO may be beneficial for patients with chronic anemia, the cost and need for PLOS ONE | DOI:10.1371/journal.pone.0119442. High doses of rHuEPO may be beneficial for patients with chronic anemia, the cost and need for PLOS ONE | DOI:10.1371/journal.pone.0119442 March 19, 2015
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