Genetic imprinting — the preferential expression of a single parental allele — has typically been implicated as an influential factor during development, but whether unequal representation of one allele can influence social behaviour has not previously been studied. The adapter protein Grb10 is predominantly expressed from the maternal allele during embryogenesis. Here, Andrew Ward and colleagues demonstrate that Grb10 is predominantly expressed from the paternal allele in the brain from fetal life onwards, and that ablating this allelic bias induces modifications to social behaviour such as grooming. This is the first report of an imprinted gene for which tissue-specific actions of each parental allele can influence distinct physiological or behavioural processes. Genetic imprinting, or the preferential expression of a single parental allele, has typically been implicated as an influential factor during development, but whether unequal representation of one allele can influence social behaviour has not been studied. Here, it is demonstrated that the adaptor protein Grb10 is predominantly expressed from the paternal allele in brain and that ablating this allelic bias induces behavioural modifications of a social nature. At this time, Grb10 is unique in the sense that tissue-specific actions of each parental allele can influence distinct physiological or behavioural processes. Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also postnatal functions including energy homeostasis2 and behaviour3,4. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success)5,6, imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues.

The Prader–Willi syndrome (PWS) genetic interval contains several brain-expressed small nucleolar (sno)RNA species that are subject to genomic imprinting. In vitro studies have shown that one of these snoRNA molecules, h/mbii-52, negatively regulates editing and alternative splicing of the serotonin 2C receptor (5htr2c) pre-RNA. However, the functional consequences of loss of h/mbii-52 and subsequent increased post-transcriptional modification of 5htr2c are unknown. 5HT_2CRs are important in controlling aspects of cognition and the cessation of feeding, and disruption of their function may underlie some of the psychiatric and feeding abnormalities seen in PWS. In a mouse model for PWS lacking expression of mbii-52 (PWS-IC^+/−), we show an increase in editing, but not alternative splicing, of the 5htr2c pre-RNA. This change in post-transcriptional modification is associated with alterations in a number of 5HT_2CR-related behaviours, including impulsive responding, locomotor activity and reactivity to palatable foodstuffs. In a non-5HT_2CR-related behaviour, marble burying, loss of mbii-52 was without effect. The specificity of the behavioural effects to changes in 5HT_2CR function was further confirmed using drug challenges. These data illustrate, for the first time, the physiological consequences of altered RNA editing of 5htr2c linked to mbii-52 loss that may underlie specific aspects of the complex PWS phenotype and point to an important functional role for this imprinted snoRNA.

Genomic imprinting results in parent-of-origin-dependent monoallelic expression of selected genes. Although their importance in development and physiology is recognized, few imprinted genes have been investigated for their effects on brain function. Gnas is a complex imprinted locus whose gene products are involved in early postnatal adaptations and neuroendocrine functions. Gnas encodes the stimulatory G-protein subunit Gsα and two other imprinted protein-coding transcripts. Of these, the Nesp transcript, expressed exclusively from the maternal allele, codes for neuroendocrine secretory protein 55 (Nesp55), a chromogranin-like polypeptide associated with the constitutive secretory pathway but with an unknown function. Nesp is expressed in restricted brain nuclei, suggesting an involvement in specific behaviors. We have generated a knockout of Nesp55 in mice. Nesp55-deficient mice develop normally, excluding a role of this protein in the severe postnatal effects associated with imprinting of the Gnas cluster. Behavioral analysis of adult Nesp55 mutants revealed, in three separate tasks, abnormal reactivity to novel environments independent of general locomotor activity and anxiety. This phenotype may be related to prominent Nesp55 expression in the noradrenergic locus coeruleus. These results indicate a role of maternally expressed Nesp55 in controlling exploratory behavior and are the first demonstration that imprinted genes affect such a fundamental behavior.