Mice Deficient in Oocyte-Specific Oligoadenylate Synthetase-Like Protein OAS1D Display Reduced Fertility

Abstract

The double-stranded RNA (dsRNA)-induced interferon response is a defense mechanism against viral infection. Upon interferon activation by dsRNA, 2′,5′-oligoadenylate synthetase 1 (OAS1A) is induced; it binds dsRNA and converts ATP into 2′,5′-linked oligomers of adenosine (called 2-5A), which activate RNase L that in turn degrades viral and cellular RNAs. In a screen to identify oocyte-specific genes, we identified a novel murine cDNA encoding an ovary-specific 2′,5′-oligoadenylate synthetase-like protein, OAS1D, which displays 59% identity with OAS1A. OAS1D is predominantly cytoplasmic and is exclusively expressed in growing oocytes and early embryos. Like OAS1A, OAS1D binds the dsRNA mimetic poly(I-C), but unlike OAS1A, it lacks 2′-5′ adenosine linking activity. OAS1D interacts with OAS1A and inhibits the enzymatic activity of OAS1A. Mutant mice lacking OAS1D (Oas1d^−/−) display reduced fertility due to defects in ovarian follicle development, decreased efficiency of ovulation, and eggs that are fertilized arrest at the one-cell stage. These effects are exacerbated after activation of the interferon/OAS1A/RNase L pathway by poly(I-C). We propose that OAS1D suppresses the interferon/OAS/RNase L-mediated cellular destruction by interacting with OAS1A during oogenesis and early embryonic development.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/.

ACKNOWLEDGMENTS

We thank Gregory Kopf and Emily Shen (Wyeth Research) for critical reading of the manuscript.

These studies were supported in part by National Institute of Health grants HD42500 to M.M.M. and HD22681 to R.M.S. and a research grant from Wyeth Research. W.Y. was supported by a postdoctoral fellowship from the Ernst Schering Research Foundation. S.A.P. was supported in part by a postdoctoral fellowship from Baylor's Center for Reproductive Biology (HD007165) and a National Research Service Award (F32 HD046335-01A1). K.H.B. was a student in the Medical Scientist Training Program at Baylor College of Medicine, supported in part by NIH training grant GM07330.