Siva plays a critical role in mouse embryonic development

Cell Death Differ. 2020 Jan;27(1):297-309. doi: 10.1038/s41418-019-0358-x. Epub 2019 Jun 4.

Abstract

The Siva protein, named after the Hindu God of Destruction, plays important roles in apoptosis in various contexts, including downstream of death receptor activation or p53 tumor suppressor engagement. The function of Siva in organismal development and homeostasis, however, has remained uncharacterized. Here, we generate Siva knockout mice to characterize the physiological function of Siva in vivo. Interestingly, we find that Siva deficiency causes early embryonic lethality accompanied by multiple phenotypes, including developmental delay, abnormal neural tube closure, and defective placenta and yolk sac formation. Examination of Siva expression during embryogenesis shows that Siva is expressed in both embryonic and extra-embryonic tissues, including within the mesoderm, which may explain the vascular defects observed in the placenta and yolk sac. The embryonic phenotypes caused by Siva loss are not rescued by p53 deficiency, nor do they resemble those of p53 null embryos, suggesting that the embryonic function of Siva is not related to the p53 pathway. Moreover, loss of the Ripk3 necroptosis protein does not rescue the observed lethality or developmental defects, suggesting that Siva may play a non-apoptotic role in development. Collectively, these studies reveal a key role for Siva in proper embryonic development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis Regulatory Proteins / physiology*
  • Embryo, Mammalian / blood supply
  • Embryo, Mammalian / metabolism
  • Embryonic Development*
  • Female
  • Genes, Lethal
  • Heart / embryology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Neural Tube / abnormalities
  • Phenotype
  • Placenta / blood supply
  • Pregnancy
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology
  • Tumor Suppressor Protein p53 / physiology
  • Yolk Sac / blood supply

Substances

  • Apoptosis Regulatory Proteins
  • Siva protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse