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

Jeyoung Bang, Minguk Han, Tack-Jin Yoo, Lu Qiao, Jisu Jung, Jiwoon Na, Bradley A Carlson, Vadim N Gladyshev, Dolph L Hatfield, Jin-Hong Kim, Lark Kyun Kim, Byeong Jae Lee

International journal of molecular sciences 2021 Oct 28

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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.

Citation

Jeyoung Bang, Minguk Han, Tack-Jin Yoo, Lu Qiao, Jisu Jung, Jiwoon Na, Bradley A Carlson, Vadim N Gladyshev, Dolph L Hatfield, Jin-Hong Kim, Lark Kyun Kim, Byeong Jae Lee. Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in Sephs1-/- Mice. International journal of molecular sciences. 2021 Oct 28;22(21)