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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 5 (September 1), 1998:
pp. 1491-1496
RAPID COMMUNICATION
The Prolactin Receptor Rescues EpoR / Erythroid
Progenitors and Replaces EpoR in a Synergistic Interaction With
c-kit
By
Merav Socolovsky,
Amy E.J. Fallon, and
Harvey F. Lodish
From the Whitehead Institute for Biomedical Research, Cambridge, MA;
and the Department of Biology, Massachusetts Institute of Technology,
Cambridge.
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ABSTRACT |
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.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
SIGNALING BY THE erythropoietin receptor
(EpoR) is essential for the production of red blood cells (RBCs).
Disruption of either the Epo or EpoR genes in mice leads to embryonic
lethality due to a severe deficiency in adult-type
erythropoiesis.1-3 The fetal livers of
Epo/ or EpoR/ mice contain normal
numbers of committed burst-forming unit erythroid (BFU-e) and
colony-forming unit erythroid (CFU-e) progenitors, but these fail to
differentiate into RBCs. Therefore, there is an essential requirement
for EpoR signaling during differentiation of committed CFU-e
progenitors.
We recently showed that wild-type BFU-e and CFU-e progenitors infected
with a retroviral construct encoding the nonhematopoietic prolactin
receptor (PrlR) respond to prolactin by differentiating into RBCs in
vitro.4 By comparing the PrlR with a chimeric receptor
containing the extracellular domain of PrlR and intracellular domain of
EpoR, we showed that the cytoplasmic domains of PrlR and EpoR are
equally efficient in supporting erythroid differentiation. There was no
difference in ligand sensitivity, colony number, morphology, or degree
of hemoglobinization between progenitors expressing either of the two
receptors.
These findings raised the intriguing possibility that there is no
requirement for an EpoR-unique signal during erythroid differentiation and, therefore, that EpoR signaling has no instructive role in erythropoiesis. However, this conclusion could not be drawn
definitively, because the above experiments were performed in wild-type
erythroid progenitors expressing the EpoR. An Epo-induced instructive
signal derived from the EpoR may have been delivered in vivo before
harvesting of erythroid progenitors.
Alternatively, although Epo was absent from the medium, it remained
possible that the EpoR was nevertheless able to generate a unique
instructive signal in an Epo-independent manner. Such a signal might
arise in a number of different ways. First, the receptor tyrosine
kinase c-kit associates with and phosphorylate the EpoR in
response to stem cell factor and in the absence of Epo.5,6
EpoR phosphorylation by c-kit does not require EpoR dimerization and is therefore distinct to its manner of activation by
Epo.7 Indeed, in the absence of stem cell factor, there is
a substantial reduction in the number of differentiated RBCs, raising
the possibility that the c-kit/EpoR interaction delivers unique, essential signals for erythroid differentiation.8,9 A second example of Epo-independent EpoR activation is provided by
gp55, the envelope protein of Friend spleen focus-forming virus (SFFV).
When coexpressed with EpoR in hematopoietic cells it renders them
factor independent. It has been suggested that an as yet unknown
endogenous protein homologous to gp55 may similarly activate EpoR.10 Finally, there may be sufficient basal activity of
the unliganded EpoR for it to generate an instructive signal.
To examine directly whether the EpoR expressed by wild-type erythroid
progenitors was essential for their terminal differentiation, we looked
at the ability of the PrlR to rescue EpoR/
erythroid progenitors. We found that the PrlR fully supported differentiation of EpoR/ progenitors into
RBCs. Therefore, there is no requirement for an EpoR-unique instructive
signal during erythroid differentiation.
Both in vivo and in vitro, maximal effects of the EpoR in erythroid
differentiation require the simultaneous activation of c-kit.
c-kit alone does not support differentiation of erythroid progenitors; however, it functionally potentiates EpoR signaling, resulting in a significant quantitative increase in the number of RBC
progeny. This is shown by the anemia of mice mutant at the W
(White-spotting) and Sl (Steel) loci.8,9 Although
c-kit interacts synergistically with many hematopoietic
cytokine receptors,9,11 the only hematopoietic phenotypic
manifestations in the W mouse are in the mast cell and
erythroid lineages. This raised the possibility that its interaction
with EpoR might be relatively unique. As noted, c-kit directly
associates with and phosphorylates the EpoR5,6; box 1 and
extended box 2 domains of EpoR are essential for the potentiation of
its signaling by c-kit in erythroid cell lines.5,12 Having found that the PrlR was quantitatively as efficient as EpoR in
supporting differentiation of EpoR/
progenitors, we asked whether, like the EpoR, it too was dependent on
c-kit activation for maximal effect. We show that this is
indeed the case. Therefore, the synergistic interaction of EpoR with c-kit does not require an EpoR-unique signal or EpoR-unique
domain.
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MATERIALS AND METHODS |
Retroviral constructs.
CHI4 (Fig 1)
contains the extracellular domain of the rabbit prolactin receptor and
membrane-spanning and intracellular domains of the murine EpoR. PrlR
encodes the rabbit prolactin receptor. Both receptors were expressed in
the retroviral expression vector MSCV.13
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| Fig 1.
PrlR and CHI, a chimeric PrlR-EpoR
receptor.16 CHI consists of PrlR extracellular domain and
EpoR transmembrane (TM) and cytoplasmic domains. Shaded rectangles
represent regions of homology with the cytokine receptor superfamily
(box 1, box 2). Cytoplasmic tyrosines are marked with a line.
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Transducing retroviruses.
VE23 ecotropic packaging cells4 were transiently
transfected using the calcium-phosphate method with MSCV retroviral
constructs each encoding the desired receptor. Culture supernatants
were collected at 48 hours and either immediately frozen or used for infection.
Mice, fetal liver cell infection, and transduced receptor
expression.
Male mice (mixed 129C/C57BL/6 background) heterozygous for the mutant
EpoR allele1 were backcrossed with either Balb/cJ or
Balb/CBYJ females. Heterozygote F1 and F2 mice were selected by
Southern blot analysis on EcoRV-digested genomic DNA, using the
cytoplasmic domain of the erythropoietin receptor as a probe. Heterozygote mice were crossed and fetal liver cells obtained from
pregnant females on day 12.5 of gestation.
Equal numbers of EpoR/ and wild-type or
heterozygote littermate fetal livers were processed in each experiment.
EpoR/ embryos were identified visually by
their extreme pallor and rudimentary fetal liver. The correct
identification of the EpoR/ embryos was
monitored by setting up a control Epo-containing culture in each
experiment. In all cases there were no Epo-dependent erythroid colonies
in the EpoR/ cultures. Retroviral infections
were performed as described.4 Briefly, fetal liver cells
were incubated with viral supernatants in the presence of 4 µg/mL
polybrene for 4 hours. We previously showed that CHI and PrlR are
equally well expressed on the surface of fetal liver cells by
fluorescence-activated cell sorter (FACS) analysis 36 hours after
infection using the M110 monoclonal antibody directed against the
extracellular domain of PrlR.4 In the present studies about
10% of the fetal liver cells were infected.
CFU-e cultures and colony scoring.
After infection, cells were washed and resuspended in semisolid
methylcellulose medium containing either 10% plasma-derived serum
(PDS) or serum-free medium as described.4 Growth factors were added to the methylcellulose medium as indicated in the text. Ovine-prolactin (National Hormone and Pituitary Program of the National
Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD)
was added at 500 ng/mL. Recombinant rat stem cell factor (Amgen,
Thousand Oaks, CA) was added at 100 ng/mL. Recombinant human Epo (Amgen) was used at 2 U/mL. Hemoglobinized CFU-e
colonies were scored on day 3 after staining with diaminobenzidine.
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RESULTS |
The prolactin receptor rescues EpoR/
progenitors.
The PrlR and a chimeric receptor, CHI, containing the PrlR
extracellular domain and EpoR membrane-spanning and intracellular domains (Fig 1), are as efficient as the EpoR in mediating
differentiation of wild-type fetal liver CFU-e progenitors in vitro.
Also, retrovirally transduced CHI and PrlR are expressed equally well
on the surface of fetal liver cells by FACS analysis using an anti-PrlR
monoclonal antibody; on average, approximately 10% of fetal liver
cells express the retrovirally transduced receptors.4 The
study in Fig 2 confirms our previous
finding that, in response to prolactin, both PrlR and CHI support full
differentiation of wild-type CFU-e progenitors.4 There is
no significant difference in the sensitivity to prolactin, CFU-e colony
numbers, colony morphology, and degree of hemoglobinization between CHI
and the PrlR.4 Figure 2A also shows that a similar result
is obtained in EpoR/ progenitors. CHI and
PrlR give rise to similar numbers of CFU-e colonies in
EpoR/ fetal liver cells in response to
prolactin. Also, the number of colonies for either receptor per
EpoR/ fetal liver is similar to the number of
colonies seen in wild-type or heterozygote fetal livers, consistent
with previous observations that EpoR/ fetal
livers contain normal numbers of CFU-e progenitors.1 The
size, morphology, and degree of hemoglobinization of the
EpoR/ colonies supported by PrlR were not
significantly different from CHI-supported colonies (Fig 2B).
Therefore, the cytoplasmic domains of PrlR and EpoR are equally
efficient in mediating differentiation of erythroid progenitors in the
absence of the wild-type EpoR.
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| Fig 2.
PrlR is as efficient as CHI in supporting
EpoR/ CFU-e colony formation. (A) Each determination
is the mean ± SEM of four independent experiments. Fetal liver cells
were cultured in methylcellulose medium containing 500 ng/mL ovine
prolactin, 100 ng/mL rat SCF (rSCF), and 10% PDS. Between 3 and 7 EpoR/ livers or livers from wild-type littermates
were used per experiment. In the presence of Epo, an average of 5,000 CFU-e colonies per wild-type fetal liver, and 12 CFU-e colonies per
EpoR/ fetal liver were obtained. Wild-type and
EpoR/ fetal livers contained an average of 2.5 × 105 and 5 × 104 nucleated cells per liver,
respectively. ( ), EpoR/; ( ),
EpoR+/ or +/+. (B)
EpoR/ CFU-e colonies supported by PrlR are
qualitatively similar to EpoR/ CFU-e colonies
supported by CHI or wild-type CFU-e colonies differentiating in
response to Epo. Scale bar: 100 µm.
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The PrlR efficiently replaces EpoR in a synergistic interaction with
c-kit.
The essential function of c-kit in erythropoiesis is thought to
be due to its ability to quantitatively potentiate the action of the
EpoR. Our finding that, in the presence of stem cell factor (SCF), PrlR
efficiently rescues EpoR/ CFU-e progenitors
(Fig 2) raised the possibility that PrlR may functionally interact with
c-kit in a manner analogous to the EpoR.
Because serum contains SCF, we first studied the effects of adding SCF
on wild-type mouse fetal liver CFU-e progenitors in either
serum-free medium or in medium containing 10% PDS. In both cases, in
the presence of a saturating Epo concentration (2 U/mL), SCF increased
the number of fetal liver CFU-e progenitors able to give rise to
differentiated colonies by approximately twofold, although the absolute
number of colonies was higher in medium with serum
(Fig 3).
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| Fig 3.
SCF potentiates the ability of Epo to support wild-type
fetal liver CFU-e colony formation. Fetal liver cells were cultured in
methylcellulose containing Epo (2 U/mL) and/or rSCF (100 ng/mL). The methylcellulose medium was either serum free, or contained
10% PDS. Results are the mean ± SD of triplicate samples.
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We proceeded to examine the effects of exogenously added SCF in this
medium, and determined the effect of SCF on prolactin-dependent differentiation of progenitors infected with either PrlR or CHI. In
progenitors derived from EpoR/ animals and
infected with either receptor, addition of SCF to the culture increased
the number of CFU-e colonies by 4.5- to 5-fold. In progenitors derived
from wild-type littermate animals and infected with either receptor,
SCF increased the number of colonies 2- to 2.5-fold
(Fig 4), similar to the effect of SCF seen
in wild-type progenitors cultured in Epo (Fig 3). There was no
significant quantitative difference between PrlR-infected and CHI-infected progenitors in their response to SCF, in either
EpoR/ or wild-type animals (Fig 4).
Therefore, PrlR is fully efficient at substituting for EpoR in a
synergistic interaction with c-kit essential for supporting
CFU-e differentiation.
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| Fig 4.
SCF potentiates the CFU-e response to prolactin in
EpoR/ and wild-type progenitors infected with either
PrlR or CHI. EpoR/ fetal liver cells or wild-type or
heterozygous littermate fetal liver cells were infected with retrovirus
encoding CHI or PrlR, and cultured in either the presence () or
absence () of SCF (100 ng/mL), in methylcellulose containing 500 ng/mL ovine-prolactin and 10% PDS. Results in each experiment were
expressed as percent of colonies obtained for wild-type fetal liver
cells infected with CHI and cultured in the presence of prolactin and
SCF. Each determination is the mean ± SD of three independent
experiments. The mean colony number per fetal liver was 540 ± 220 for
PrlR-infected cells and 660 ± 198 for CHI-infected cells.
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DISCUSSION |
EpoR does not play an instructive role in erythroid differentiation.
Our principal finding is that a nonhematopoietic receptor, the PrlR,
can rescue EpoR/ erythroid progenitors in
vitro. The cytoplasmic domain of the PrlR was as efficient as the
cytoplasmic domain of EpoR in supporting the full differentiation of
EpoR/ CFU-e progenitors, with no significant
quantitative or qualitative difference in the resulting erythroid
colonies. In EpoR/ progenitors the PrlR was
also efficiently able to substitute for the EpoR in a synergistic
interaction with c-kit, which is essential for normal
erythropoiesis. This confirms and expands our previous finding that a
retrovirally transduced PrlR can support the differentiation of
wild-type CFU-e progenitors.4 It directly shows for the
first time that there is no EpoR-unique function required for erythroid
differentiation. Instead, the essential role of EpoR signaling in RBC
differentiation must be supportive. The signals generated by EpoR are
presumably "generic" and may also be induced by other cytokine
receptors. Although there is little sequence homology between the
cytoplasmic domains of EpoR and PrlR, both receptors activate a very
similar set of downstream signaling molecules, including JAK2 and
STAT5; these are also activated by many other cytokine
receptors.14-18
Therefore, the specificity of EpoR action in erythropoiesis is a result
of its unique expression by erythroid progenitors. The unique outcome
of EpoR signaling is presumably a result of the unique cellular
environment in the erythroid progenitors in which it acts. The precise
functions supported by these "generic" EpoR signals are still to
be fully determined, but include anti-apoptotic19 as well
as mitogenic20 effects, functions common to many cytokine receptors. The unique cellular context of a committed progenitor may
also allow a nonunique signal to result in tissue-specific gene
induction.
Supportive signaling by other cytokine receptors.
Recent reports suggest that our findings regarding the lack of an
instructive role for EpoR in differentiation may be extended to other
cytokine receptors. Mice mutant for the interleukin-7 (IL-7) receptor
show severe lymphocyte deficiency; transgenic expression of bcl-2 in T
cells of these mice rescued T-cell lymphocyte development and reversed
the lymphopenic phenotype.21,22 Similarly, the low
macrophage and osteoclast cell numbers found in the op/op (macrophage colony-stimulating factor [M-CSF] deficient) mouse can be
restored by transgenic expression of bcl-2 in macrophage progenitors.23 Therefore, the essential function of these
cytokine receptors is to ensure survival of progenitors, while lineage commitment and maturation events occur by other means. In contrast, transgenic expression of bcl-2 in the erythroid lineage did not result
in Epo independence.24 Taken together with the results presented here, it may indicate that the signals generated by EpoR,
although not unique, are not exclusively concerned with progenitor cell
survival. Alternatively, additional non-bcl-2 anti-apoptotic pathways
may be operating in erythroid cells.
The absence of instructive signaling by lineage-restricted cytokine
receptors raises the question of how lineage commitment is determined.
We cannot exclude a role for as yet unknown extracellular factors in
this process. Alternatively, lineage commitment may occur
stochastically, as first proposed by Till and others.25-28 The expression of lineage-restricted cytokine receptors would be a
manifestation of lineage commitment rather than its cause, and would
allow specific cytokines to selectively rescue and amplify the
progenitors of a particular lineage according to physiological need.
Support for this comes from experiments in which expression of an
activated EpoR or M-CSF receptor by pluripotent
progenitors did not bias differentiation in favor of the lineages to
which they are physiologically restricted; instead, it caused an
overall increase in differentiated cell numbers.27
The role of c-kit in erythroid differentiation.
The activation of c-kit by SCF plays a unique role in
erythropoiesis. The principal effect of c-kit is quantitative:
RBCs are formed in its absence, but are fewer in number, as shown by the macrocytic anemia of mice mutant at the W (White-spotting) and Sl (Steel) loci, respectively.8,9 The
severity of the different allelic forms of W mice correlates with the degree of impairment of kinase activity of the mutant c-kit.29-31 c-kit exerts its effects at the
BFU-e and CFU-e stages of erythropoiesis: 80% to 90% of BFU-e and
CFU-e progenitors express c-kit,32 fetal livers of
W mice contain significantly reduced numbers of CFU-e
progenitors,8 and although the number of adult marrow CFU-e
in W/Wv mice is normal, they have a markedly
reduced response to Epo.33 In vitro, c-kit
potentiates the proliferative and anti-apoptotic effects of EpoR, a
synergistic interaction that had been shown in primary erythroid
progenitors as well as erythroid cell lines.6,11,12,34,35
c-kit is widely expressed and interacts synergistically with
many other cytokine receptors, including those for IL-3, IL-6, IL-7,
granulocyte-macrophage CSF (GM-CSF), and G-CSF.10,11 However, the hematopoietic deficiencies in W mice are confined to the erythroid and mast cell lineages, raising the possibility that
the synergistic interaction of c-kit with the EpoR might be
relatively unique. The precise molecular mechanism of this synergistic
interaction is not known, but may involve direct association of the two
receptors, as well as phosphorylation of the EpoR by c-kit.5,6 Box 1 and the extended box 2 domains of
EpoR are essential for the potentiation of its signaling by
c-kit in erythroid cell lines.5,12
The relatively greater SCF dependence of
EpoR/ CFU-e progenitors when compared to
wild-type littermate progenitors (Fig 4) had been previously seen in
EpoR/ progenitors rescued by retrovirally
transduced EpoR.7 It may be due to a requirement for
simultaneous signaling by the two receptors. In wild-type animals, but
not in EpoR/ animals, some simultaneous
activation of c-kit and EpoR in vivo may have preceded
harvesting of progenitors, allowing a greater number of CFU-e cells to
subsequently mature in vitro in the absence of SCF.
Our finding that PrlR can quantitatively replace the EpoR in its
synergistic interaction with c-kit in both wild-type and EpoR/ progenitors suggests that this
interaction does not require an EpoR-unique domain or signal. The
unique outcome of c-kit signaling in the erythroid lineage
cannot be explained by a unique molecular interaction with the EpoR.
Conversely, c-kit's association with and phosphorylation of
EpoR5,6 may turn out to be features of its synergistic
interactions with other cytokine receptors.
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FOOTNOTES |
Submitted April 21, 1998;
accepted June 2, 1998.
Supported by Grant No. HL 32262 from The National Institutes of Health,
by a grant from Amgen Corporation, and in part by a Howard Hughes
postdoctoral fellowship for physicians (M.S.).
Address reprint requests to Harvey F. Lodish, PhD, Whitehead Institute
for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142;
e-mail: lodish{at}wi.mit.edu.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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ACKNOWLEDGMENT |
We thank Drs Stefan Constantinescu and Saghi Ghaffari for discussion
and comments on the manuscript.
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Abstract
Introduction
Abstract