A minimal cytoplasmic subdomain of the erythropoietin receptor mediates erythroid and megakaryocytic cell development

Signals provided by the erythropoietin (Epo) receptor are essential for the development of red blood cells, and at least 15 distinct signaling factors are now known to assemble within activated Epo receptor complexes. Despite this intriguing complexity, recent investigations in cell lines and retrov irally transduced murine fetal liver cells suggest that most of these facto rs and signals may be functionally nonessential. To test this hypothesis in erythroid progenitor cells derived from adult tissues, a truncated Epo rec eptor chimera (EE372) was expressed in transgenic mice using a GATA-1 gene- derived vector, and its capacity to support colony-forming unit-erythroid p roliferation and development was analyzed. Expression at physiological leve ls was confirmed in erythroid progenitor cells expanded ex vivo, and this E E372 chimera was observed to support mitogenesis and red blood cell develop ment at wild-type efficiencies both independently and in synergy with c-Kit . In addition, the activity of this minimal chimera in supporting megakaryo cyte development was tested and, remarkably, was observed to approximate th at of the endogenous receptor for thrombopoietin. Thus, the box 1 and 2 cyt oplasmic subdomains of the Epo receptor, together with a tyrosine 343 site (each retained within EE372), appear to provide all of the signals necessar y for the development of committed progenitor cells within both the erythro id and megakaryocytic lineages. (C) 1999 by The American Society of Hematol ogy.