Hum. Reprod. Advance Access originally published online on February 13, 2008
Human Reproduction 2008 23(4):807-818; doi:10.1093/humrep/den009
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Profound phenotypic variation among mice deficient in the maintenance of genomic imprints
1 McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada H3H 1P3 2 Department of Pediatrics, McGill University, Montreal, Quebec, Canada H3H 1P3 3 Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3H 1P3 4 Department of Pharmacology and Therapeutics McGill University, Montreal, Quebec, Canada H3H 1P3 5 Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA 15261, USA 6 Department of Biological Sciences Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, PA 15213, USA 7 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA
8 Correspondence address. Tel: +1-412-383-7974; Fax: +1-412-383-7984; E-mail: chaillet{at}pitt.edu (J.R.C.)
BACKGROUND: An alteration in the mechanism that maintains the monoallelic, imprinted expression of genes can result in their biallelic expression and lead to disruptions in fetal development. Here, we examined the consequences of a loss of maintenance methylation at one specific stage of preimplantation, induced by a deficiency of the oocyte-derived Dnmt1o protein and known to produce biallelic expression of imprinted genes.
METHODS: Phenotypes of mid-gestation Dnmt1o-deficient mouse embryos were assessed by a scoring system based on the developmental stage of 17 anatomical features and by magnetic resonance microscopy.
RESULTS: Many mid-gestation embryos developing without Dnmt1o protein exhibited significant developmental delays of multiple organ systems (P < 0.05) and a wide variety of morphologic anomalies compared with wild-type embryos. Most of the remaining mid-gestation Dnmt1o-deficient embryos appeared normal.
CONCLUSIONS: These findings indicate that a profound range of gestational phenotypes can be induced by the loss of a single protein at a specific preimplantation developmental stage. This is best explained by the formation of epigenetic mosaic early embryos, composed of somatic cells with different spectra of normal intact genomic imprints. These findings have important implications for understanding the types of embryonic phenotypes related to the disruption of inherited imprints, and thus may provide a model of altered imprinting in humans. In particular, because Dnmt1o functions in the preimplantation embryo, a complete or partial loss of Dnmt1o function may play a role in epigenetic abnormalities seen in assisted reproduction technology births.
Key words: imprinting/embryogenesis/phenotype/birth defect/epigenetic
Submitted on September 17, 2007; resubmitted on December 28, 2007; accepted on January 10, 2008.