Wellcome CRC Institute; University of Cambridge
Three imprinted genes have so far been identified on proximal chromosome 7. Peg3 was the first gene to be identified which encodes a C2H2 type zinc finger protein and it exhibits paternal allele-specific expression. We also recently detected another novel paternally expressed gene, Oat, which maps at 200 bp upstream of Peg3 and that is transcribed in the opposite direction to Peg3. In addition, a Kruppel-type-zinc-finger gene, Zim1, has also been reported within 30 kb downstream of Peg3, but this gene shows expression of the maternal allele only. Expression patterns of all these three genes are dissimilar which suggests that their expression is regulated by distinct gene-specific control elements. We are investigating the organization and mechanism of imprinting of these genes, and their functions during development and in adults.
Peg3 is the most extensively studied gene so far within this region. It consists of 9 exons spanning 26 kb and the 5' region is differentially methylated with the silent maternal copy being methylated. We also demonstrated that mice inheriting a mutant Peg3 paternal allele were growth retarded, and the females showed a striking impairment of maternal behavior frequently resulting in death of the offspring. This may be in part due to reduced oxytocin neurones in the hypothalamus as mothers were also deficient in milk ejection. The deficit in maternal behavior including nest building, pup retrieval and thermal protection was also observed in virgin and multiparous females, implicating other defects in neuronal connectivity in mutant mice.