Biology Reference
In-Depth Information
Molecular biology of the erythropoietin receptor in
hematopoietic and non-hematopoietic tissues
Christof Dame
Division of Neonatology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA;
and Department of Neonatology, Humboldt University, Charité Campus Virchow, Augustenburger
Platz 1, D-13353 Berlin, Germany
Introduction
Reports on the identification, characterization, and cloning of human erythro-
poietin (EPO) were published in 1985 [1, 2]. Four years later the murine EPO
receptor (EPOR) was identified and cloned,and this was followed soon by
reports of cloning human EPOR [3-6]. The biology of the EPO/EPOR system
remains of great interest, not only because of the importance in erythropoietic
regulation, but because a broad range of non-hematopoietic effects of this sys-
tem have become evident [7, 8]. Non-hematopoietic effects of EPO may have
a significant potential in treating various disorders, including spinal cord
injury, asphyxia, stroke, and neurodegenerative or retinal diseases [9-12]. This
chapter summarizes current data on the molecular and cellular biology of
EPOR as a key element in transmitting the effects of EPO. Specific focus is
given to developmental-stage dependent, tissue-specific, and environmental
aspects of EPOR in non-hematopoietic organs.
The implication of EPO and EPOR in hematopoiesis
The crucial role of EPO and EPOR for normal development is indicated by the
fact that in mice, homozygous deletion of the
EPO
gene (EPO
-/-
) or
EPOR
gene (EPOR
-/-
) results in fetal death between day 10.5 and 13.5 of gestation
[13-16]. In the absence of EPO or EPOR, commitment of hematopoietic pro-
genitors (CFU-GEMM) to the erythroid lineage is intact, erythropoiesis pro-
gresses
in vitro
through the stage of erythroid burst-forming units (BFU-E),
but terminates at the stage of erythroid colony-forming units (CFU-E). In mice
with targeted homozygous deletions of the
EPO
or
EPOR
gene, “primitive”
erythropoiesis is established, but “definitive” erythropoiesis is not [13, 15, 17].
The growth of early EPOR
-/-
erythroid progenitor cells can to some degree be
compensated by thrombopoietin (TPO) alone or in combination with other
growth factors such as stem cell factors (SCF) or interleukin (IL)-3 plus IL-11
