Somatic Reactivation of Expression of the Silent Maternal <i>Mest</i> Allele and Acquisition of Normal Reproductive Behaviour in a Colony of <i>Peg1/Mest</i> Mutant Mice

Abstract

Abstract. Genomic imprinting confers allele-specific expression in less than 1% of genes, in a parent-of-origin specific fashion. In humans and mice the Peg1/Mest gene (Mest) is maternally repressed, and paternally expressed. Mest is expressed in embryogenic mesoderm-derived tissues and in adult brain, and paternal mutations in Mest lead to growth retardation and defective maternal behaviour. Despite our current understanding of mechanisms associated with the establishment of imprinting of Mest and other imprinted genes, it is unclear to what extent Mest imprinting needs to be maintained in adult tissues. Aberrations of imprinting are known to occur in certain rare syndromes, and involve either inherited mutations, or constitutive epigenetic alterations occurring soon after fertilization. Imprinting abnormalities may also occur in the aging somatic tissues of adult individuals. Here we report an occurrence of post-embryonic somatic variability of Mest allelic expression in a colony of mice where heterozygotes at the imprinted Mest locus for a mutation inherited from the father spontaneously expressed the normally silenced allele from the mother. In addition, a newly acquired ability to overcome the deficit in maternal reproductive behaviour had occurred in the mutant mice, but this appeared not to be directly linked to the Mest mutation. Our results suggest that at least one allele of Mest expression is required in the somatic tissues of adult individuals and that under certain conditions (such as in the presence of a Mest insertional mutation or in an altered genetic background), somatically acquired alterations of allelic expression at the Mest locus may occur. Key words: Adult brain expression, Epigenetic, Imprinting, Maternal behaviour, Somatic expression, Peg1/Mest (J. Reprod. Dev. 58: [490][491][492][493][494][495][496][497][498][499][500] 2012) I n mammals the mesoderm-specific locus, Paternally expressed gene 1 (Peg1/Mest; hereafter called Mest), transcribes a maternally imprinted gene expressed in the mesoderm lineage during embryogenesis, and in adult tissues, such as brain [1]. The precise function of Mest is unknown, although its gene product has similarity to the α/β hydrolase family of proteins [2]. Knock out studies in mice show that Mest is important for proper tissue growth and adult maternal reproductive behaviour [3]. Mest +/tm1Lef heterozygous mutant mice carrying a non-functional paternally inherited mutant allele (denoted here as Mest +/-) display retarded growth, and in females a reduction of their reproductive fitness caused by failure to nurture or care for pups [3], whereas conversely heterozygous mutant mice with the maternally inherited mutant allele Mest tm1Lef/+ (denoted here as Mest -/+ ) are normal, because Mest is a paternally expressed gene.While reproductive fitness is an important trait for species survival, relatively little is known about the role of genomic imprinting in reproductive fitness. Stochastic errors of imprinting or other spontaneous imprinting epimutations, s...

Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest)

“…The reasons for differences between our targeted Mest mouse model and Mest tm1Lef are not well understood but could be due to differences in the genetic background of the mice, the gene targeting construct, or mutation(s) in the host ES cell used for targeting [61]. Recently it was reported that backcrossing targeted Mest tm1Lef mice 5 generations onto a129/SVJ background also eliminated the early postnatal lethality and maternal behavioral phenotypes of mice with a paternal inactivation of Mest ; however, the explanation why this occurred was not clearly defined [62]. …”

Mest/Peg1 Is Essential for the Development and Maintenance of a SNc Neuronal Subset

“…The maternal allele is silenced via extensive methylation of the promoter region, which is established after fertilization (Lefebvre et al, 1997, 1998). Methylation of the maternal allele is normally permanent, although it has been shown that heterozygous mice that do not have a functional paternal allele can show expression of Mest after E13.5, indicating that imprinting of the maternal allele can be reversed under certain conditions (Imamura et al, 2005; Ineson et al, 2012). Mest knock-out (KO) mice are viable and, apart from growth retardation, have not been reporter to show obvious phenotypic features (Lefebvre et al, 1998).…”

DNA methylation abnormalities of imprinted genes in congenital heart disease: A pilot study

“…MEST is a maternal imprinted gene and widely expressed throughout the embryonic period [24]. Mest-knockout mice exhibited embryonic and placental growth retardation and postnatal growth inhibition, while loss of the imprinted gene resulted in postnatal weight gain and multiple organ hypertrophy [25,26]. King et al have found that Mest speci cally expressed myocardial trabeculae in developing atria and ventricles of mice.…”