Biology Reference
In-Depth Information
Central nervous system
Among non-hematopoietic tissues, the biology of EPO in the central nervous
system (CNS) has been most intensively investigated, and recent reviews
report on these findings [7, 154]. EPO expression in the CNS underlies a tis-
sue-specific regulation under normoxia and hypoxia as well [139, 155,156].
The EPO protein produced by neurons and astrocytes is biological active
[157]. By immunochemical analysis in PC12 cells (an EPO-expressing rat
pheochromocytoma cell line which can differentiate into a neuronal pheno-
type), solubilized EPOR showed to be smaller (62 Kd) than that on rat ery-
throid cells (68 Kd). Moreover, the affinity of rEPO to EPOR on neuronal cells
was found to be lower as on erythroid cells [158].
The effects of EPO are mediated by the expression of EPOR, which is abun-
dant in the embryonic, fetal,and adult CNS as it has been shown in rats, mice,
monkeys, and humans [155, 156, 159-161]. A temporal and cellular distribu-
tion of EPOR in the human embryonic, fetal,and adult CNS has been identi-
fied. In the embryonic cerebral hemisphere, EPOR expression has been local-
ized to undifferentiated neuroepithelial cells in the periventricular germinal
zone at five to six weeks pc [161, 162], from where neuronal regeneration
takes place [163]. At 10 weeks of gestation, EPOR is localized primarily to the
subventricular zone, the neuropil, and the cortical plate, while only low expres-
sion was found in the ventricular and matrix zone. Immunoreactivity of the
hippocampus and nucleus caudatus is weak or not found at this stage of devel-
opment. As development proceeds, the diffuse staining of broad zones of the
developing neocortex is replaced by more specific cellular staining of increas-
ingly differentiated neurons. EPOR expression can be detected in sub-popula-
tions of astrocytes within and around brain capillaries [161, 164]. EPOR
immunoreactivity has been found within the astrocytic foot processes sur-
rounding the capillaries and also within endothelial cells [164]. Intense
immunoreactivity for EPOR has been found in neurons (in a pattern restricted
to the somata and proximal dendrites) and the choroid plexus [162, 164]. The
pattern of cellular staining seems to be shifted from astrocytes, which are pre-
dominantly stained for EPOR early in development, to neurons in the mature
brain [161, 162, 165]. In adult humans,
EPOR
gene expression has been
described in the hippocampus, amygdala, and temporal cortex [156, 162].
However, the level of EPOR expression in human adult bone marrow is
two-fold higher than the level detected in adult brain as determined by quanti-
tative RT-PCR analysis [166].
The developmental regulation of EPOR expression in the CNS has been
confirmed in animal models. While EPOR expression can be detected at day E
10.5 in the embryonic mouse brain at similar levels as in hematopoietic tissue,
but EPOR mRNA levels in the CNS decrease significantly with further devel-
opment [167]. Because EPOR transcripts have a relatively short half-life of
about 90 minutes in erythroid cells, the gene must be continuously transcribed
to maintain high expression levels [168]. A region flanking the human EPOR
