Biology Reference
In-Depth Information
proximal promotor (exon 1 to exon 2) is necessary to actively drive EPOR
expression [160]. The proximal promotor of the EPOR gene is functional intact
in the CNS, but underlies an alternate processing or reduction in splicing effi-
ciency compared with EPOR on erythroid progenitor cells. In the human brain,
EPOR transcripts can be initiated by a region far upstream of the EPOR prox-
imal promoter (exon A and exon B). The expression of these transcripts in com-
parison to transcripts from the EPOR encoding regions (exon 1 to exon 2) is
developmentally regulated. In the adult brain, transcripts of the proximal pro-
moter region are expressed 10-fold lower than in the developing brain [166].
These data indicate that the biological effectiveness of EPO in the CNS may be
regulated - at least in part - by EPOR expression levels.
In vitro
studies in NT2
cells, a human neuronal precursor cell line that expresses EPO, showed that
EPOR expression in neuronal cells can be induced on the transcriptional level
by GATA-3 binding to the minimal EPOR region. Conversely, lack of EPOR
down-regulates GATA-3 expression in cortical cells, suggesting specific and
complex mechanisms of EPOR gene regulation in neuronal cells [114].
Experimental studies indicate a crucial role of the EPO/EPOR system in the
normal CNS. Binding of endogenous EPO by soluble EPOR renders EPO less
available to the developing CNS cells, and treated adult rats show neuronal
degeneration and impaired learning [169]. Mice with targeted homozygous
deletion of the
EPOR
gene suffer from extensive apoptosis in the developing
brain. As early as day E10.5 the number of neuronal progenitor cells has been
reported as reduced, while apoptosis increased.
In vivo
, neuronal generation
from cortical cells is decreased,while the sensitivity to low oxygen tension is
increased, resulting in cell death [114]. In contrast, the proliferation of brain
derived cells from EPOR
-/-
mice, taken at day E11.5-13.5 of gestation, is nor-
mal [16]. Differences between these both studies may be due to the fact that
EPOR expression peaks in the murine CNS during mid-gestation or that dif-
ferent cortical cell lineages were selected. Another study gave evidence that
EPO regulates the
in vivo
and
in vitro
production of neuronal progenitors by
mammalian forebrain neural stem cells [170]. A recent study shows surpris-
ingly normal brain development in EPOR
-/-
mice rescued from the lethal
hematopoietic defect by using a blood-specific regulatory element of the
GATA-1 promoter to drive EPOR expression [22]. Further analysis of these
animals is necessary to elucidate the cause for this discrepancy and answer the
question whether EPOR in the CNS is primary relevant under stressful condi-
tions as hypoxia or ischemia in the non-rescued EPOR
-/-
fetuses [171].
Various
in vivo
and
in vitro
studies indicate that EPO exerts its trophic and
cell-protective effects in the injured CNS by a variety of mechanisms, includ-
ing antiapoptotic and anti-inflammatory mechanisms, and immune or electro-
physiological modulation [7, 11, 154, 158, 159, 164, 169, 172-181]. Changes
in EPOR expression play a key regulatory element in activating these mecha-
nisms.
In situ
hybridization analysis showed the up-regulation of EPOR and its
continuous expression (at 24 hours after brain injury) in the periphery
(ischemic penumbra) of the cerebrocortical infarct area in the adult murine
