Brain-expressed imprinted genes and adult behaviour: the example of Nesp and Grb10

Abstract

Imprinted genes are defined by their parent-of-origin-specific monoallelic expression. Although the epigenetic mechanisms regulating imprinted gene expression have been widely studied, their functional importance is still unclear. Imprinted genes are associated with a number of physiologies, including placental function and foetal growth, energy homeostasis, and brain and behaviour. This review focuses on genomic imprinting in the brain and on two imprinted genes in particular, Nesp and paternal Grb10, which, when manipulated in animals, have been shown to influence adult behaviour. These two genes are of particular interest as they are expressed in discrete and overlapping neural regions, recognised as key "imprinting hot spots" in the brain. Furthermore, these two genes do not appear to influence placental function and/or maternal provisioning of offspring. Consequently, by understanding their behavioural function we may begin to shed light on the evolutionary significance of imprinted genes in the adult brain, independent of the recognised role in maternal care. In addition, we discuss the potential future directions of research investigating the function of these two genes and the behavioural role of imprinted genes more generally.

The landscape of genomic imprinting across diverse adult human tissues

“…While many studies have characterized imprinting in early development and its functional role, for example, in placental function and fetal growth, our results shed light on patterns of imprinting in adults, which have been shown to have functional consequences as well (Ubeda and Gardner 2011;Dent and Isles 2014). The patterns of imprinting discovered in this study provide additional empirical data for evaluating theories for evolutionary causes for imprinting (Bartolomei and Ferguson-Smith 2011;Patten et al 2014).…”

Genomic imprinting in development, growth, behavior and stem cells

“…Recent work has also shown that paternal deletion of Grb10, which is expressed from the paternal allele in a subset of neurons from alternative promoter(s), is associated with hyper-aggression and increased social dominance in mice (Garfield et al, 2011). Finally, a maternally expressed gene, Nesp (Gnas), which encodes a protein involved in neuro-excretory function, is associated with novel exploration behavior and has been observed to have striking overlap in expression with Grb10 in the brain (Dent and Isles, 2014;Plagge et al, 2005).…”

Germline-derived DNA methylation and early embryo epigenetic reprogramming: The selected survival of imprints

“…Imprinted DMRs can influence expression by acting as methylation-sensitive insulators (such as the paternally methylated H19 DMR) (Hark et al, 2000) or alternatively as promoters of ncRNA which recruit epigenetic regulators (such as the maternally methylated DMR associated with Kcnq1ot1) (Lee et al, 1999). Imprinted genes have been shown to influence not only early embryonic development and placental function, but impact on behavior and metabolic adaption later in life (Constância et al, 2004;Madon-Simon et al, 2014;Dent and Isles, 2014). Therefore it is likely that genome-wide disruption to imprinted gene expression is the principal cause of defects observed in methylation-deficient knockout mice (Kaneda et al, 2004).…”