Endogenous retroviruses regulate periimplantation placental growth and differentiation

doi:10.1073/pnas.0603836103

Endogenous retroviruses regulate periimplantation placental growth and differentiation

*Center for Animal Biotechnology and Genomics, Department of Animal Science, and
^‡Image Analysis Laboratory, Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843; and
^†Institute of Comparative Medicine, University of Glasgow Veterinary School, Glasgow G61 1QH, United Kingdom

Edited by George E. Seidel, Jr., Colorado State University, Fort Collins, CO, and approved August 8, 2006 (received for review May 10, 2006)

Abstract

Endogenous retroviruses (ERVs) are fixed and abundant in the genomes of vertebrates. Circumstantial evidence suggests that ERVs play a role in mammalian reproduction, particularly placental morphogenesis, because intact ERV envelope genes were found to be expressed in the syncytiotrophoblasts of human and mouse placenta and to elicit fusion of cells in vitro. We report here in vivo and in vitro experiments finding that the envelope of a particular class of ERVs of sheep, endogenous Jaagsiekte sheep retroviruses (enJSRVs), regulates trophectoderm growth and differentiation in the periimplantation conceptus (embryo/fetus and associated extraembryonic membranes). The enJSRV envelope gene is expressed in the trophectoderm of the elongating ovine conceptus after day 12 of pregnancy. Loss-of-function experiments were conducted in utero by injecting morpholino antisense oligonucleotides on day 8 of pregnancy that blocked enJSRV envelope protein production in the conceptus trophectoderm. This approach retarded trophectoderm outgrowth during conceptus elongation and inhibited trophoblast giant binucleate cell differentiation as observed on day 16. Pregnancy loss was observed by day 20 in sheep receiving morpholino antisense oligonucleotides. In vitro inhibition of the enJSRV envelope reduced the proliferation of mononuclear trophectoderm cells isolated from day 15 conceptuses. Consequently, these results demonstrate that the enJSRV envelope regulates trophectoderm growth and differentiation in the periimplantation ovine conceptus. This work supports the hypothesis that ERVs play fundamental roles in placental morphogenesis and mammalian reproduction.

Footnotes

^§To whom correspondence should be addressed. E-mail: tspencer{at}tamu.edu
Author contributions: K.A.D., M.P., M.V., and T.E.S. designed research; K.A.D., M.P., M.V., R.C.B., K.H., J.L.F., and T.E.S. performed research; M.P., M.V., R.C.B., K.H., J.L.F., and T.E.S. contributed new reagents/analytic tools; K.A.D., M.P., M.V., and T.E.S. analyzed data; and K.A.D., M.P., and T.E.S. wrote the paper.
The authors declare no conflict of interest.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ERV,

endogenous retrovirus;

JSRV,

Jaagsiekte sheep retrovirus;

enJSRV,

endogenous retrovirus related to JSRV;

BNC,

binucleate cell;

MAO,

morpholino antisense oligonucleotide;

CSH,

chorionic somatomammotropin hormone;

PAG,

pregnancy-associated glycoprotein.