Abstract
EphAs and ephrin-As have been implicated in the morphogenesis of the developing brain. We found that EphA7 and ephrin-A5 are coexpressed in the dorsal midline (DM) of the diencephalon and anterior mesencephalon. Interestingly, programmed cell death (PCD) of the neural epithelial cells normally found in this region was reduced in ephrin-A5/ephrin-A2 dual-deficient embryos. In contrast, in vivo expression of ephrin-A5-Fc or full-length ephrin-A5 strongly induced apoptosis in neural epithelial cells and was accompanied by severe brain malformation during embryonic development. Expression of ephrinA5-Fc correlated with apoptosis of EphA7-expressing cells, whereas null mutation of ephrin-A5 resulted in the converse phenotype. Importantly, null mutation of caspase-3 or endogenous ephrin-A5 attenuated the PCD induced by ectopically overexpressed ephrin-A5. Together, our results suggest that brain region-specific PCD may occur in a region where EphAs cluster with neighboring ephrin-As through cell–cell contact.
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Abbreviations
- BAC:
-
bacterial artificial chromosome
- BrdU:
-
5-bromo-2′-deoxyuridine
- DM:
-
dorsal midline
- DR5:
-
death receptor 5
- EGF:
-
epidermal growth factor
- Eph:
-
erythropoietin-producing hepatocellular kinase
- ephrin:
-
Eph receptor interacting proteins
- FADD:
-
Fas-associated death domain
- GFP:
-
green fluorescent protein
- NEC:
-
neural epithelial cell
- NGF:
-
nerve growth factor
- NTC:
-
neural tube closure
- NTCD:
-
neural tube closure defect
- PCD:
-
programmed cell death
- PCR:
-
polymerase chain reaction
- p75NTR:
-
p75 neurotrophin receptor
- RTK:
-
receptor tyrosine kinase
- TNFR-1:
-
tumor necrosis factor receptor 1
- Trk:
-
tropomyosin receptor kinase
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
- X-gal:
-
5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside
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Acknowledgements
We are indebted to Jonas Frisen and Pierre Vanderhaeghen for ephrin-A5 knock-out mice and human ephrin-A5 cDNA, respectively. This work was supported by a grant (no. 2009-0083149) from National Research Foundation of Korea (NRF), a grant (no. 2009K001246) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology, and a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare (A111706).
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Park, E., Kim, Y., Noh, H. et al. EphA/ephrin-A signaling is critically involved in region-specific apoptosis during early brain development. Cell Death Differ 20, 169–180 (2013). https://doi.org/10.1038/cdd.2012.121
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DOI: https://doi.org/10.1038/cdd.2012.121
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