Abstract
Radiation therapy (RT) is pivotal in the treatment of many central nervous system (CNS) pathologies; however, exposure to RT in children is associated with a higher risk of secondary CNS tumors. Although recent research interest has focused on the reparative and therapeutic role of microglia, their recruitment following RT has not been elucidated, especially in the developing CNS. Here, we investigated the spatiotemporal dynamics of microglia during tissue repair in the irradiated embryonic medaka brain by whole-mount in situ hybridization using a probe for Apolipoprotein E (ApoE), a marker for activated microglia in teleosts. Three-dimensional imaging of the distribution of ApoE-expressing microglia in the irradiated embryonic brain clearly showed that ApoE-expressing microglia were abundant only in the late phase of phagocytosis during tissue repair induced by irradiation, while few microglia expressed ApoE in the initial phase of phagocytosis. This strongly suggests that ApoE has a significant function in the late phase of phagocytosis by microglia in the medaka brain. In addition, the distribution of microglia in p53-deficient embryos at the late phase of phagocytosis was almost the same as in wild-type embryos, despite the low numbers of irradiation-induced apoptotic neurons, suggesting that constant numbers of activated microglia were recruited at the late phase of phagocytosis irrespective of the extent of neuronal injury. This medaka model of microglia demonstrated specific recruitment after irradiation in the developing CNS and could provide a useful potential therapeutic strategy to counteract the detrimental effects of RT.
Highlights
IntroductionMicroglia in the Irradiated Embryonic Brain developing secondary cancers associated with ionizing radiation
Radiation therapy (RT) is a widely accepted treatment for many central nervous system (CNS) pathologies, there are significant detrimental effects such as an increased risk of PLOS ONE | DOI:10.1371/journal.pone.0127325 June 10, 2015Microglia in the Irradiated Embryonic Brain developing secondary cancers associated with ionizing radiation
We demonstrated that many apoptotic cells were induced by irradiation, especially in the marginal area of the optic tectum (OT) visualized using an acridine orange (AO) assay; phagocytic cells had eliminated them almost completely by the time of hatching
Summary
Microglia in the Irradiated Embryonic Brain developing secondary cancers associated with ionizing radiation. Following any kind of brain damage or injury stimulus, microglia switch to an activated state, become amoeboid in morphology, and migrate toward the site of injury to engulf and eliminate neuronal debris after apoptotic cell death [8, 9]. Previous studies in the mouse have revealed a longitudinal pattern of increased numbers of microglia derived from bone marrow cells to the site of injury in the brain after exposure to radiation. Previous reports using zebrafish as a model revealed the recruitment of microglia in the developing CNS when restricted local trauma was induced [11]; their recruitment in response to radiation exposure has not been elucidated. We investigated the spatiotemporal behavior of activated microglia after irradiation in the developing brain using the medaka embryo as a model
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