Biology Reference
In-Depth Information
“undetectable” in one publication (
77
) - an opinion not shared by
the majority of researchers working in the field (
78
). Recent data
advocates that the tissue protective non-hematopoietic receptor is
distinct from the hematopoietic receptor responsible for erythro-
poiesis being a heterodimer consisting of the beta common recep-
tor subunit (bCR also known as CD131) in combination with the
EpoR subunit (see Fig.
1
and reviewed by ref.
75
). A variety of
tissues have been found to express bCR and EpoR including the
central and peripheral nervous system, retina, heart, kidney, mus-
cle, and endothelium. Notably, the important role of the bCR in
Epo-mediated protection has been demonstrated in brain injury
models using bCR knockout mice (
79, 80
) as well as in endothe-
lium using siRNA technology (
81
). However the downstream
signaling mechanisms activated by bCR are still to be elucidated.
When EpoR is not colocalized with bCR it presumably self-associates
forming the classical EpoR homodimer that also supports signaling
(reviewed by ref.
75
).
The importance of EpoR specifically in non-hematopoietic tis-
sues has been recently investigated using transgenic mice with EpoR
expression restricted to hematopoietic tissues and the vascular
endothelium. These mice survive without any gross abnormalities
but become obese and insulin resistant due to loss of Epo regula-
tion of energy homeostasis (
82
). It should be noted however that
because endothelial cells have the same origin as hematopoietic cells
these mice still express EpoR on vascular endothelium. Recent stud-
ies using these mice in heart ischemia-reperfusion injury model
(
83
) and traumatic brain injury model (
84
) identify the endothe-
lium as a major contributor to Epo-mediated protection and sup-
porter of significant tissue recovery from injury. More experiments
are now needed in various injury paradigms to better understand
the contribution of the homoreceptor, heterodimer, and the
endothelium per se to tissue protection during Epo treatment.
5
Brain
5.1 Endogenous
Production of Epo
in CNS
Epo and EpoR have been detected during early brain development
in rodent models. Both are also expressed during human fetal devel-
opment starting around 7 weeks and increase from 8 to 24 weeks
(
43
). After birth Epo was detected in human cerebral spinal fluid
and found to be induced by hypoxia (
5
). Notably, Epo and EpoR
expression persist in the human brain throughout adulthood.
Mouse models showed that knockout of either gene caused
embryonic death not only due to erythropoiesis failure but also as
a result of compromised brain development. In these models the
neurons exhibited intrinsic defects such as slowed proliferation and
increased sensitivity to hypoxic stress (
85
). Additionally a specific
deficit in post-stroke neurogenesis by the impaired migration of
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