The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit.
We recently showed that a retrovirally transduced prolactin receptor (PrlR) efficiently supports the differentiation of wild-type burst-forming unit erythroid (BFU-e) and colony-forming unit erythroid (CFU-e) progenitors in response to prolactin and in the absence of erythropoietin (Epo). To examine directly whether the Epo receptor (EpoR) expressed by wild-type erythroid progenitors was essential for their terminal differentiation, we infected EpoR-/- progenitors with retroviral constructs encoding either the PrlR or a chimeric receptor containing the extracellular domain of the PrlR and intracellular domain of EpoR. In response to prolactin, both receptors were equally efficient in supporting full differentiation of the EpoR-/- progenitors into erythroid colonies in vitro. Therefore, there is no requirement for an EpoR-unique signal in erythroid differentiation; EpoR signaling has no instructive role in red blood cell differentiation. A synergistic interaction between EpoR and c-kit is essential for the production of normal numbers of red blood cells, as demonstrated by the severe anemia of mice mutant for either c-kit or its ligand, stem cell factor. We show that the addition of stem cell factor potentiates the ability of the PrlR to support differentiation of both EpoR-/- and wild-type CFU-e progenitors. This synergism is quantitatively equivalent to that observed between c-kit and EpoR. Therefore, there is no requirement for an EpoR-unique signal in the synergistic interaction between c-kit and EpoR.
Whitehead Institute for Biomedical Research, Cambridge, MA; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
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D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011388:Prolactin / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D017467:Receptors, Erythropoietin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011981:Receptors, Prolactin / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology
D017467:Receptors, Erythropoietin; D011981:Receptors, Prolactin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D011388:Prolactin; D019009:Proto-Oncogene Proteins c-kit