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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3381-3387
A Minimal Cytoplasmic Subdomain of the Erythropoietin Receptor Mediates
Erythroid and Megakaryocytic Cell Development
Chris P. Miller,
Zi Y. Liu,
Constance T. Noguchi, and
Don M. Wojchowski
From the Programs in Genetics and Cell and Developmental Biology, The
Pennsylvania State University, University Park, PA; and the Laboratory
of Chemical Biology, NIDDK, National Institutes of Health, Bethesda,
MD.
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 retrovirally transduced murine fetal
liver cells suggest that most of these factors and signals may be
functionally nonessential. To test this hypothesis in erythroid progenitor cells derived from adult tissues, a truncated Epo receptor chimera (EE372) was expressed in transgenic mice using a GATA-1 gene-derived vector, and its capacity to support colony-forming unit-erythroid proliferation and development was analyzed. Expression at physiological levels was confirmed in erythroid progenitor cells
expanded ex vivo, and this EE372 chimera was observed to support
mitogenesis and red blood cell development at wild-type efficiencies
both independently and in synergy with c-Kit. In addition,
the activity of this minimal chimera in supporting megakaryocyte development was tested and, remarkably, was observed to approximate that of the endogenous receptor for thrombopoietin. Thus, the box 1 and
2 cytoplasmic subdomains of the Epo receptor, together with a tyrosine
343 site (each retained within EE372), appear to provide all of the
signals necessary for the development of committed progenitor cells
within both the erythroid and megakaryocytic lineages.
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