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J. Biol. Chem., Vol. 282, Issue 35, 25875-25883, August 31, 2007

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Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation^*

Zhi-Yong Chen, Pundit Asavaritikrai, Josef T. Prchal, and Constance Tom Noguchi¹

From the Molecular Medicine Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1822 and Department of Medicine, Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas 77030

Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoR-null mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extra-hematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.

Received for publication, March 7, 2007 , and in revised form, June 28, 2007.

^* This work was supported by the intramural research program of NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Molecular Medicine Branch, NIDDK, National Institutes of Health, Bldg. 10, Rm. 9N307, 10 Center Dr., MSC-1822, Bethesda, MD 20892-1822. Tel.: 301-496-1163; Fax: 301-402-0101; E-mail: cnoguchi{at}helix.nih.gov.

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