The Absence of the Oocyte-derived Dnmt1o Protein Leads to Anatomical and Molecular Abnormalities in Placentae.

MARTEL, J; FORTIER, A; LOPES, F; CIRIO, MC; CHAILLET, JR; TRASLER, J

Congreso; Society for the Study of Reproduction (SSR); 2008

The Dnmt1o DNA cytosine methyltransferase protein, a variantof the larger somatic Dnmt1s methyltransferase is derived fromthe oocyte and present in high concentrations in preimplantationembryos. Dnmt1o maintains parental, sex-specific genomic imprintsduring preimplantation development. Mid-gestation embryos developingin the absence of Dnmt1o have significant delays in developmentand a wide range of anatomical abnormalities. We previouslyshowed that Dnmt1o deficiency is associated with abnormal methylationof imprinted genes and variable biallelic expression of H19and Snrpn in 9.5 dpc embryos and their placentae. The goal ofthis study was to further examine the effects of Dnmt1o deficiencyon extraembryonic tissues, in particular on placental development.Female mice lacking oocyte-derived Dnmt1o as well as controlfemales were crossed with wild-type 129/Sv males; embryos andplacentae were collected at day 9.5 of gestation. When comparedto control placentae, we observed that the lack of the oocyteform of the Dnmt1 protein leads to interesting placental abnormalities.Thirty-seven placentae (from 19 female and 18 male embryos)were obtained from eight litters of Dnmt1o-deficient females.Fifteen of the 37 placentae were abnormal, being larger thancontrol and/or encompassing the embryo ("shell-shaped"). Forty-sevenpercent of the female and 33% of the male placentae showed suchabnormalities. "Shell-shaped" placentae were more common amongfemale than male placentae (32% versus 11%). Taken together,these finding strongly suggest imprinting defects due to theloss of Dnmt1o lead to profound anatomical (and likely physiological)abnormalities in the placentae. Moreover, the increased incidenceof abnormalities in female placentae suggests that the absenceof Dnmt1o may also lead to defects in epigenetic control ofgenes on the X chromosome. Serial sectioning and further histologicalanalysis are currently being performed. We propose that mouseembryos developing in the absence of Dnmt1o are important modelsof the type of both embryonic and extra-embryonic phenotypesthat might be expected in humans due to the post-zygotic disruptionof genomic imprinting. (Supported by the NIH and CIHR)