Functional characterization of D630023F18Rik in the DNA damage response and brain development

Embryonic brains are sensitive to ionizing radiation. As a consequence, prenatal radiation exposure leads to neurological effects like microcephaly, defects in brain morphology, cognitive defects, or epilepsy. For this reason, pregnant women are so protected from ionizing radiation and get negative advice for radiotherapy. The tumor suppressor gene P53, a transcription factor, is the main regulator of the so-called DNA damage response, which is triggered after DNA damage due to i.a. ionizing radiation. In 2015, a new gene, D630023F18Rik, was discovered as a novel P53 target upon exposure of the brains of mouse embryos to ionizing radiation. Furthermore, under normal conditions, D630023F18Rik expression is restricted to the brain and kidneys, but upon whole body irradiation, D630023F18Rik is upregulated in many tissues. This suggests it has an important role in the radiation response at the organism level. In addition, the expression of D630023F18Rik is highly upregulated during brain development, and several of its protein interaction partners are important for proper brain function indicating that D630023F18Rik may also be important for proper brain development. Together, this suggests that the misregulation of this gene after prenatal radiation exposure could play a role in the observed brain development defects. During this project, we aim to investigate the biological and physiological functions of D630023F18Rik in the DNA damage response and normal brain development. For this, different experimental models will be used, including D630023F18Rik knockout mice, primary neuronal progenitor cell cultures, and mouse embryonic stem cells. The results of this research will help us to understand the function of the hitherto uncharacterized D630023F18Rik gene. This may provide fundamental insight to determine if D630023F18Rik is a possible pharmaceutical target for neurological defects after radiation exposure. As last, it will improve our understanding of the P53 pathway in specific cells and maybe uncover associated pathways.