International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 19 - ROLE OF DE NOVO DNA METHYLTRANSFERASES IN GENOMIC IMPRINTING REVEALED BY CONDITIONAL GENE KNOCKOUT IN MICE

Sasaki H
1) National Institute of Genetics, 2) Graduated University for Advanced Studies

Co-Authors: 1,2) Kaneda M, 1,2) Sado T, 3) Okano M, 1) Hata K, 4) Li E
Institutions: 1) National Institute of Genetics, 2) Graduated University for Advanced Studies, 3) RIKEN, 4) Massachusetts General Hospital

DNA methylation marks the imprinted genes differently during male and female gametogenesis, and the epigenetic differences (imprints) between the two gametes lead to parental-origin-specific gene expression in the offspring. However, since disruptions of DNA methyltransferases (Dnmt1, 3a and 3b) in mice resulted in embryonic or early postnatal lethality, their effect on the establishment of imprints in the germline has not been studied. To circumvent this problem, we took advantage of the Cre-loxP system and inactivated the two de novo DNA methyltransferases preferentially in the germline. The resulting conditional knockout mice ([Dnmt3a2lox/-, TNAP-Cre] and [Dnmt3b2lox/-, TNAP-Cre]) were viable and reached the reproductive age. Successful inactivation of the 2lox alleles in the germline and the resulting homozygous state of the germ cells were confirmed by PCR. Interestingly, offsprings from the conditional Dnmt3a females crossed with wildtype males lacked the maternal methylation imprints and died around e8.5-9.5. The conditional Dnmt3a males, on the other hand, showed impaired spermatogenesis and were infertile. These phenotypes resembled those of the Dnmt3L-/- mice, which lack a methyltransferase-related protein with no methylase activity. By clear contrast, the conditional Dnmt3b knockout mice showed no apparent phenotype and their offsprings grew normally. These results demonstrate that Dnmt3a plays a crucial role in the establishment of the maternal imprints.


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