Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in Sephs1−/− Mice

International Journal of Molecular Sciences

Vadim N. Gladyshev¹  Jeyoung Bang²  Minguk Han²  Byeong Jae Lee²  Dolph L. Hatfield³  Bradley A. Carlson³  Lu Qiao⁴  Jin-Hong Kim⁴  Jiwoon Na⁴  Tack-Jin Yoo⁴  Jisu Jung⁴  Lark Kyun Kim⁵ 

[1] Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul 08826, Korea;Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea;Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Korea;

关键词: selenium;    selenoprotein;    SEPHS1;    early embryogenesis;    embryonic lethality;    reactive oxygen species;   

DOI  :  10.3390/ijms222111647

来源: DOAJ

【 摘 要 】

Selenophosphate synthetase 1 (SEPHS1) plays an essential role in cell growth and survival. However, the underlying molecular mechanisms remain unclear. In the present study, the pathways regulated by SEPHS1 during gastrulation were determined by bioinformatical analyses and experimental verification using systemic knockout mice targeting Sephs1. We found that the coagulation system and retinoic acid signaling were most highly affected by SEPHS1 deficiency throughout gastrulation. Gene expression patterns of altered embryo morphogenesis and inhibition of Wnt signaling were predicted with high probability at E6.5. These predictions were verified by structural abnormalities in the dermal layer of Sephs1^−/− embryos. At E7.5, organogenesis and activation of prolactin signaling were predicted to be affected by Sephs1 knockout. Delay of head fold formation was observed in the Sephs1^−/− embryos. At E8.5, gene expression associated with organ development and insulin-like growth hormone signaling that regulates organ growth during development was altered. Consistent with these observations, various morphological abnormalities of organs and axial rotation failure were observed. We also found that the gene sets related to redox homeostasis and apoptosis were gradually enriched in a time-dependent manner until E8.5. However, DNA damage and apoptosis markers were detected only when the Sephs1^−/− embryos aged to E9.5. Our results suggest that SEPHS1 deficiency causes a gradual increase of oxidative stress which changes signaling pathways during gastrulation, and afterwards leads to apoptosis.

【 授权许可】

Unknown