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.
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We are grateful to Ching-Pin Chang, Kryn Stanukas, and Jill Helms for helpful comments. We thank Jacqueline Benjamin, Tiara Kawahara, Samantha Brugmann, Elora Majumder, and Sean Massa for technical assistance.
This work was supported by the Giannini Family Foundation to SBRJ, the NSF and NIH (1F31CA167917-01) to JLVN, and the Damon Runyon Cancer Research Foundation, the Donald E. and Delia B. Baxter Foundation, and the NIH (5R03NS05618002 and R35 CA197591) to LDA.
Conflict of interest
The authors declare that they have no conflict of interest.
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Edited by G. Melino