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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	selenium selenoprotein SEPHS1 early embryogenesis embryonic lethality reactive oxygen species Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/b9546de268e0439ea6d7559a6bd87738
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spelling	oai:doaj.org-article:b9546de268e0439ea6d7559a6bd877382021-11-11T17:07:12ZIdentification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice10.3390/ijms2221116471422-00671661-6596https://doaj.org/article/b9546de268e0439ea6d7559a6bd877382021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11647https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Selenophosphate 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 <i>Sephs1</i>. 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 <i>Sephs1<sup>−/−</sup></i> embryos. At E7.5, organogenesis and activation of prolactin signaling were predicted to be affected by <i>Sephs1</i> knockout. Delay of head fold formation was observed in the <i>Sephs1<sup>−/−</sup></i> 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 <i>Sephs1<sup>−/−</sup></i> 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.Jeyoung BangMinguk HanTack-Jin YooLu QiaoJisu JungJiwoon NaBradley A. CarlsonVadim N. GladyshevDolph L. HatfieldJin-Hong KimLark Kyun KimByeong Jae LeeMDPI AGarticleseleniumselenoproteinSEPHS1early embryogenesisembryonic lethalityreactive oxygen speciesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11647, p 11647 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	selenium selenoprotein SEPHS1 early embryogenesis embryonic lethality reactive oxygen species Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	selenium selenoprotein SEPHS1 early embryogenesis embryonic lethality reactive oxygen species Biology (General) QH301-705.5 Chemistry QD1-999 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 <i>Sephs1<sup>−/−</sup></i> Mice
description	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 <i>Sephs1</i>. 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 <i>Sephs1<sup>−/−</sup></i> embryos. At E7.5, organogenesis and activation of prolactin signaling were predicted to be affected by <i>Sephs1</i> knockout. Delay of head fold formation was observed in the <i>Sephs1<sup>−/−</sup></i> 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 <i>Sephs1<sup>−/−</sup></i> 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.
format	article
author	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
author_facet	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
author_sort	Jeyoung Bang
title	Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice
title_short	Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice
title_full	Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice
title_fullStr	Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice
title_full_unstemmed	Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice
title_sort	identification of signaling pathways for early embryonic lethality and developmental retardation in <i>sephs1<sup>−/−</sup></i> mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b9546de268e0439ea6d7559a6bd87738
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Identification of Signaling Pathways for Early Embryonic Lethality and Developmental Retardation in <i>Sephs1<sup>−/−</sup></i> Mice

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