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Blood, 15 July 2001, Vol. 98, No. 2, pp. 475-477
BRIEF REPORT
The human erythropoietin receptor gene rescues erythropoiesis and
developmental defects in the erythropoietin receptor null
mouse
Xiaobing Yu,
Chyuan-Sheng Lin,
Frank Costantini, and
Constance Tom Noguchi
From the Laboratory of Chemical Biology, National
Institute of Diabetes and Digestive and Kidney Disorders,
National Institutes of Health, Bethesda, MD; and the Department of
Genetics and Development, Columbia University, New York, NY.
 |
Abstract |
Erythropoietin and its receptor are required for definitive
erythropoiesis and maturation of erythroid progenitor cells. Mice lacking the erythropoietin receptor exhibit severe anemia and die at
about embryonic day 13.5. This phenotype can be rescued by the human
erythropoietin receptor transgene. Animals expressing only the human
erythropoietin receptor survived through adulthood with normal
hematologic parameters and appeared to respond appropriately to induced
anemic stress. In addition to restoration of erythropoiesis during
development, the cardiac defect associated with embryos lacking
the erythropoietin receptor was corrected and the increased apoptosis
in fetal liver, heart, and brain in the erythropoietin receptor null
phenotype was markedly reduced. These studies indicate that no species
barrier exists between mouse and human erythropoietin receptor and that
the human erythropoietin receptor transgene is able to provide specific
expression in hematopoietic and other selected tissues to rescue
erythropoiesis and other organ defects observed in the erythropoietin
receptor null mouse.
(Blood. 2001;98:475-477)
© 2001 by The American Society of Hematology.
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Introduction |
Absence of erythropoietin or the erythropoietin
receptor (EpoR) results in interruption of definitive erythropoiesis in
the fetal liver,1,2 defective cardiac
development,3 and eventual death at about embryonic day
13.5 (E13.5). Unlike interleukin-3 and granulocyte macrophage
colony-stimulating factor, erythropoietin is cross-reactive between
species. We hypothesize that the human EpoR (hEpoR) is equivalent to
the mouse EpoR (mEpoR) and that it can rescue the developmental defects
in liver and heart of the EpoR null mouse (mEpoR /) and
restore normal hematopoietic development. An 80-kb hEpoR transgene
recapitulates EpoR expression in hematopoietic tissue with high levels
in yolk sac and fetal liver, and then adult spleen and bone marrow
following the site of hematopoiesis.4 This transgene
includes 6 kb of 5' flanking sequence containing the proximal promoter
that provides much of the transcription activity in erythroid
cells.5-7 We show that the hEpoR transgene restores effective erythropoiesis in the EpoR null mouse and normalizes cardiac
as well as brain development. These results illustrate that the mouse
and human EpoRs are nearly equivalent and provide evidence for
erythropoietin multiorgan function.
| |
Study design |
The rescue mEpoR/, hEpoR+ genotype
was obtained by mating mEpoR+/2 and hEpoR
transgenic mice containing an 80-kb hEpoR gene fragment,4 and intercrossing mEpoR+/, hEpoR+, and
mEpoR+/ mice. Genotyping by polymerase chain reaction
(PCR) analyses of tail DNA used null mEpoR primers2 and
the hEpoR primers4 as described previously. For embryos,
yolk sac DNA was used. For TdT-mediated d-UTP nick end labeling
(TUNEL) analysis,8 embryo sections were treated
with proteinase K and analyzed using digoxigenin-labeled dUTP with
terminal deoxynucleotidyl transferase (Roche Molecular Biochemicals,
Indianapolis, IN), followed by incubation with antidigoxigenin antibody
conjugated with alkaline phosphatase (Dako Corporation, Carpinteria,
CA). New fuchsin substrate reaction was used to visualize positive
staining, and sections were counterstained with hematoxylin.
Adult progenitor cell colony assays of bone marrow were carried out in
triplicate cultures in Methocult GF M3434 or Methocult M3334 (Stemcell
Technologies, Vancouver, BC, Canada) and monitored after 2 days for
erythroid colony-forming unit (CFU-E) and after 12 days for erythroid
burst-forming unit (BFU-E). Quantitative reverse transcriptase
PCR was used for expression analysis of total RNA isolated from bone
marrow, spleen, brain, heart, lung, kidney, and skeletal muscle, as
described previously.9 Gene-specific primers and
fluorescent labeled Taqman probes (7700 Sequence Detector; PE Applied
Biosystems, Foster City, CA) spanning exon junctions were as follows:
for hEpoR, forward primer, 5'-GCT CCC TTT GTC TCC TGC T-3'; reverse
primer, 5'-CTC CCA GAA ACA CAC CAA GTC CT-3'; probe, 5'-AGC GGC CTT GCT
GGC GG-3'. Primers and probe for mEpoR were described
previously.9 To induce anemia, mice were injected with
phenylhydrazine (Sigma, St Louis, MO) at a dose of 0.04 mg/g of body
weight for 5 days.4 Mice were killed on day 7. Blood samples were collected for hematology and erythropoietin detection. Serum erythropoietin concentrations were determined by enzyme-linked immunosorbent assay using anti-human erythropoietin antibody (R&D Systems, Minneapolis, MN). Tissues were harvested and analyzed for EpoR expression.
| |
Results and discussion |
The hEpoR transgene rescued the mEpoR/ genotype,
normalized hematopoiesis, and increased survival through adulthood with
no gross malformations. Although some initial difficulty in mating these mice was encountered, males and females were both fertile. The
hEpoR transcript was processed to its mature form in hematopoietic cells.10 Appropriate hematopoietic expression suggests
that regulatory elements in the transgene are sufficient to mimic
endogenous EpoR expression, which may be useful in constructing vectors
to drive gene expression, particularly in early erythroid progenitor cells where EpoR expression is maximal.11 The
hEpoR-rescued mice exhibited normal hematologic parameters (Figure
1A). Hematopoietic colony culture showed
that BFU-E and CFU-E progenitors, and CFU-granulocyte, macrophage (CFU-GM) and CFU-granulocyte, erythroid, macrophage, and
megakaryocyte (CFU-GEMM), were also analogous to those in normal controls (Figure 1B). Although some specificity for
erythropoietin/EpoR has been observed for other species,12
the rescue of the EpoR/ genotype by the hEpoR transgene
indicates that there is no apparent species barrier between mouse and
human with regard to erythropoietin stimulation of its receptor. Only
minimal differences in erythropoietin levels following anemic stress
were detected (Figure 1E). These results contrast with the report that
murine erythropoietin is 10-fold less active than human erythropoietin
on human cells.13
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| Figure 1.
Hematopoiesis in the mEpoR/,
hEpoR+ mouse.
(A) Hematologic parameters for the mEpoR/,
hEpoR+ (hEpoR+) genotype were comparable to
those of wild-type (WT) controls. (B) CFU-E colonies (left) and BFU-E,
CFU-GM, and CFU-GEMM colonies (right) were determined for bone marrow
hematopoietic progenitor cells (n = 5). (C) EpoR expression was
determined for spleen (Spl), bone marrow (BM), brain (Br), and heart
(Ht) for wild-type controls (mEpoR) (n = 3) and
mEpoR/, hEpoR+ (hEpoR) mice (n = 3), amol
indicates attomoles. (D) Phenylhydrazine-induced (PHZ) anemia in
mEpoR/, hEpoR+ mice (n = 3) increased
hEpoR expression in hematopoietic tissues and brain (n = 3 for
control). (E) Results of stimulation of erythropoiesis in
phenylhydrazine-treated mice were similar in
mEpoR/, hEpoR+ mice and controls
as indicated by reticulocyte counts and hematocrit. Only differences in
circulating erythropoietin levels (about 2-fold higher in
mEpoR/, hEpoR+ mice compared with controls)
were detected. Serum erythropoietin levels in untreated mice were not
detected in this assay because of the relatively low affinity of the
antibody for murine erythropoietin.
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Quantitative analysis showed high hEpoR expression in adult
hematopoietic tissues (spleen and bone marrow) comparable to mEpoR in
normal controls (Figure 1C). Significant levels of hEpoR transcripts were also observed in the heart. Although transgene expression in adult
brain was low, this was considerably higher than in other nonhematopoietic tissue such as skeletal muscle (data not shown). Like
endogenous EpoR, the hEpoR transgene responded to anemic stress.
Animals subjected to phenylhydrazine treatment to induce anemia
exhibited an increase in hEpoR expression of 5-fold in spleen and of
24-fold in bone marrow (Figure 1D), with comparable erythropoietic
activity and increased reticulocyte count (Figure 1E). Although no
increase in hEpoR expression was observed in the heart, a 3-fold
induction of hEpoR expression was observed in the brain, comparable to
increases we had observed previously in normal mice.4
Recovery from anemia in these mice was similar to that in treated
controls. During development, endogenous EpoR and the hEpoR transgene
are expressed in embryonic heart and brain in addition to hematopoietic
tissue.3,4 These data suggest that the regulatory elements
in the hEpoR transgene provide appropriate temporal and tissue-specific
expression, including the response to anemic stress.
The mEpoR/ mice exhibited a pale yolk sac and embryo
(Figure 2A) with increased apoptosis
(TUNEL-positive cells) in the fetal liver (Figure 2C) by E12.5. In
contrast, circulating erythroid cells were readily observed in the yolk
sac blood vessels and in fetal liver of the mEpoR/,
hEpoR+ embryo (Figure 2B), with little apoptosis in the
fetal liver (Figure 2D). Expression of hEpoR in adult heart and brain
led us to examine these tissues during development. By E11.5,
ventricular hypoplasia was noted in mEpoR/ mice and in
erythropoietin null mice, indicating a defect in proliferation and
expansion of the myocardium.3 We identified extensive
apoptosis in the myocardium and endocardium of the
mEpoR/ embryonic heart (Figure 2E). In comparison,
expression of the hEpoR transgene normalized the proliferation of
endocardium and myocardium (Figure 2F), confirming a role for EpoR in
heart development. Erythropoietin stimulation of
cardiomyocytes,14 of satellite cells or myoblasts
from skeletal muscle,9 of endothelium,15,16 and of neovascularization in vivo17 provides additional
support for a broader role for erythropoietin in stimulating the
proliferation of progenitor cells before terminal differentiation.
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| Figure 2.
Analyses of
mEpoR/, hEpoR+ embryos.
(A,B) The mEpoR/ pale embryo (A) at E12.5 contrasts
with the erythroid-rich mEpoR/, hEpoR+
embryo (B). (C-H) The increased apoptotic activity (TUNEL-positive
cells) in the mEpoR/ fetal liver (C), heart (E), and
brain (G) is rescued by the hEpoR transgene, with reduced
TUNEL-positive cells in the corresponding fetal liver (D), heart (F),
and brain (H). The bar in (C) indicates 0.05 mm.
|
|
During development, we readily observed TUNEL-positive cells in
the neuroepithelial tissues of the EpoR/ mouse (Figure
2G), accompanied by hypoplasia in the region of the fourth ventricle.
This increase in apoptosis in the developing brain was also rescued by
the hEpoR transgene, and both the mEpoR/,
hEpoR+ and normal controls had few apoptotic cells in
corresponding sites in the nervous system (Figure 2H). These results
suggest a neuroprotective and/or proliferative effect of
erythropoietin, as observed in culture of NT2 cells treated with
hypoxia18 and in primary embryonic neural cultures with
enhanced dopamine neuron generation.19 In adults,
erythropoietin is produced on both sides of the blood-brain barrier
and is hypoxia inducible,20 and erythropoietin
administration has been shown to be neuroprotective in animals when
challenged with ischemia or other injury to the brain.21-23 In addition to induction of EpoR in the brain
by anemic stress (Figure 1D), hypoxia induces EpoR expression and
increases erythropoietin sensitivity in neuronal cell
cultures.18 The expression of EpoR in heart and brain and
the associated apoptosis in the mEpoR/ mouse during
development provide evidence for a multiorgan response to erythropoietin.
To date, the only species-distinct activity for EpoR is interaction
with the spleen focus forming virus (SFFV) gp55-P viral envelope
protein, which is specific for mouse but not human EpoR.24 Other viruses or pathogens may target the hEpoR, such as gene-transfer vectors incorporating human erythropoietin on their
surface.25 Like SFFV, these interactions may exhibit
preferential binding or interactions in a species-dependent manner. The
rescue of the mEpoR/ mouse by the human transgene
provides a model system to examine interactions specific to the hEpoR.
| |
Footnotes |
Submitted December 12, 2000; accepted March 12, 2001.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Constance Tom Noguchi, Laboratory of Chemical
Biology, National Institute of Diabetes and Digestive and Kidney
Disorders, National Institutes of Health, Bethesda, MD 20892-1822;
e-mail: cnoguchi{at}helix.nih.gov.
| |
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Top
Abstract
Introduction