Human cytokine receptor CRLF3 is a receptor for the neuroprotective erythropoietin splice variant EV-3

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Cytokine receptor like factor 3 (CRLF3) is a conserved cytokine receptor present in all major eumetazoan taxa. Though vertebrate CRLF3 has recently been implied in the regulation of hematopoiesis, its ligand remained unidentified. CRLF3 shares structural similarity with receptors for other hematopoietic growth factors including erythropoietin, thrombopoietin and granulocyte colony-stimulating factor. Besides hematopoietic organs, these established hematopoietic cytokines and their receptors are also widely expressed in other tissues including the nervous system, where they regulate proliferation, differentiation, cell survival and other homeostatic processes. Previous studies identified insect CRLF3 as a neuroprotective receptor that can be activated by human recombinant erythropoietin, a widely accepted protective cytokine in vertebrate nervous systems. Epo’s erythropoietic functions mediated by classical Epo receptor are understood in great detail whereas Epo-mediated cytoprotective mechanisms are more complex due to involvement of additional Epo receptors and a splice variant (EV-3) with selectivity for certain unidentified receptors. In the present study, we show that human CRLF3 mediates neuroprotection upon activation with the natural Epo splice variant EV-3. We generated CRLF3 knock out iPSC lines and differentiated them towards the neuronal lineage. While apoptotic death of rotenone-challenged wild type iPSC-derived neurons was prevented by EV-3, EV-3-mediated neuroprotection was absent in CRLF3 knock out neurons. Rotenone-induced apoptosis and EV-3-mediated neuroprotection were associated with differential expression of pro- and anti-apoptotic genes. Our data characterize human CRLF3 as a receptor involved in Epo-mediated neuroprotection and identify CRLF3 as the first known receptor for EV-3.