The 8-Oxoguanine DNA Glycosylase 1(OGG1 ) Decreases The Vulnerability Of The Developing Brain And Heart To DNA Damage

Part I: The 8-oxoguanine DNA glycosylase 1(ogg1) decreases the vulnerability of the developing brain to DNA damageThe developing brain is particularly vulnerable to oxidative DNA damage, which may be the cause of most major congenital mental anomalies. Among the three main repair pathway including: 1) direct repair; 2) base excision repair; 3) nucleotide excision repair, the highly conserved base-excision repair pathway initiated by the repair enzyme OGG1 is the key repair pathway. However, its function in the embryonic brain is largely unknown. This study is the first to validate the function of ogg1 during brain development by using zebrafish embryos.By applying whole mount in situ hybridization(WISH), ogg1 was found to be highly expressed in the brain throughout early embryonic development(17 hpf- 48 hpf), with particularly enrichment observed in the midbrain. The lack of ogg1 caused severe brain defects including changes in brain volume and integrity, destruction of the midbrain–hindbrain boundary, and balance and motor impairment, while overexpression of ogg1 could partially rescue these defects. Multiple cellular and molecular events were involved in the manifestation of brain defects due primarily to the lack of ogg1. These included(1) increased apoptosis;(2) decreased proliferation; and(3) aberrant axon distribution and extension from the inner surface towards the outer layers. The results of a microarray analysis showed that the expression of genes involved in cell cycle checkpoint, apoptosis, and neurogenesis were significantly changed in response to ogg1 knockdown. Cmyb was the key downstream gene that responses to DNA damage caused by ogg1 deficiency. Notably, the recruitment of ogg1 m RNA could alleviate the effects on the brain due to neural DNA damage.In summary, we introduced here that ogg1 was fundamentally required for protecting the developing brain, which might be helpful in understanding the aetiology of congenital brain defects.PartⅡ: 8-Oxoguanine DNA glycosylase 1(ogg1) maintains the function of cardiac progenitor cells during heart formation in zebrafishGenomic damage may devastate the potential of progenitor cells and consequently impair early organogenesis. We found that OGG1, a key enzyme initiating the base-excision repair, was enriched in the embryonic heart in zebrafish. So far, little is known about DNA repair in cardiogenesis. Here, we addressed the critical role of ogg1 in cardiogenesis for the first time. Ogg1 mainly expressed in the anterior lateral plate mesoderm(ALPM), the primary heart tube, and subsequently the embryonic myocardium by WISH. Loss of ogg1 resulted in severe cardiac morphogenesis and functional abnormalities, including the short heart length, arrhythmia, decreased cardiomyocytes and nkx2.5+ cardiac progenitor cells. Moreover, the increased apoptosis and repressed proliferation of progenitor cells caused by ogg1 deficiency might contribute to the heart phenotype. The microarray analysis showed that the expression of genes involved in embryonic heart tube morphogenesis and heart structure were significantly changed due to the lack of ogg1. Among those, foxh1 was an important partner of ogg1 in the cardiac development in response to DNA damage. Our work demonstrated the requirement of ogg1 in cardiac progenitors and heart development in zebrafish. These findings might be helpful for understanding the aetiology of congenital cardiac defects.