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Erythropoietin receptor signalling is required for normal brain development
Xiaobing Yu1, John J Shacka, Jeffrey B Eells
1Laboratory of Chemical Biology, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
Development (Cambridge, England)
|January 25, 2002
Summary
Erythropoietin (EPO) protects developing brains by stimulating neural progenitor cells and preventing cell death. This neuroprotection is evident early in embryonic development and is enhanced under hypoxic conditions.
Area of Science:
- Neuroscience
- Developmental Biology
- Hematology
Background:
- Erythropoietin (EPO) is known for its role in red blood cell production and has demonstrated neuroprotective effects in adult models of brain ischemia.
- The function of EPO during embryonic brain development is unclear, despite high expression of its receptor in the developing brain.
Purpose of the Study:
- To investigate the role of erythropoietin (EPO) and its receptor in embryonic brain development and its potential neuroprotective functions.
- To determine if EPO influences neural progenitor cell survival and apoptosis during embryonic development.
Main Methods:
- Analysis of erythropoietin receptor knockout (Epor-/-) mice, examining embryonic brain development, cell apoptosis, and neural progenitor cell numbers.
- In vitro studies using primary cortical neuron and neural progenitor cell cultures from Epor-/- and wild-type (Epor+/+) embryos.
- Assessment of cell viability, neuron generation, and apoptosis under normoxic and hypoxic conditions, with and without EPO stimulation.
Main Results:
- Epor-/- mice exhibit severe anemia, cardiac defects, and embryonic lethality by E13.5, with significant apoptosis in the fetal brain by E12.5.
- Absence of EPO receptor leads to reduced neural progenitor cells and increased apoptosis in the embryonic brain as early as E10.5.
- In vitro, Epor-/- cortical cultures showed decreased neuron generation and heightened sensitivity to hypoxia, with no neuronal survival after 24 hours of hypoxia. EPO stimulation increased viability of wild-type neurons and promoted proliferation of progenitor cells, particularly under hypoxia.
Conclusions:
- Erythropoietin (EPO) plays a crucial role in stimulating neural progenitor cells and preventing apoptosis in the developing embryonic brain.
- The neuroprotective effects of EPO are present early in development (E10.5) and are enhanced under hypoxic stress.
- Hypoxia-induced upregulation of EPO and its receptor may be a mechanism for selective cell survival in the developing brain.