Endogenous Erythropoietin Signaling Is Required for Normal Neural Progenitor Cell Proliferation

Zhi-Yong Chen,Pundit Asavaritikrai,Josef T Prchal,Constance Tom Noguchi

doi:10.1074/jbc.m701988200

Abstract

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.

Highlights

Epo2 is a hypoxia responsive cytokine required for production of erythroid cells
To determine whether the increased apoptosis in embryonic brain and affected brain development are due to anemia in utero and lack of oxygen delivery or due to endogenous Epo signaling in brain or neural cells, we developed mice that expressed EpoR driven by the endogenous EpoR promoter in hematopoietic tissue but not in the central nervous system
Neural Progenitor Cells Express Higher Level of Epo Receptors than Mature Neurons—We used a primary hippocampal cell culture system to evaluate whether EpoR is expressed in mature neurons or neural progenitor cells (NPCs)

Summary

Introduction

Epo2 is a hypoxia responsive cytokine required for production of erythroid cells. It triggers erythroid progenitor cell proliferation and differentiation by binding to its specific membrane receptor EpoR. Epo Signaling Affects Neuron Development—Previously we demonstrated that embryonic brain of EpoR-null mice exhibited increased apoptosis, and neural cultures from these mice at E10.5 showed increased sensitivity to hypoxia suggesting an intrinsic defect during embryonic neural development as an indirect consequence of disrupted EpoR expression in hematopoietic/erythroid progenitor cells or possibly due to loss of Epo signaling in neural cells [8].

Results

Conclusion