Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

Abstract

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 post-natal 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 to date no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adapter protein that can interact with a number of 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 to date a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, due to actions of the two parental alleles in different tissues.

Tissue-specific regulation and function of Grb10 during growth and neuronal commitment

“…Of note, nearly all monoaminergic cell populations within the midbrain and hindbrain show paternal Grb10 expression (6). Additionally, Grb10 paternal expression is excluded from the cortex both during development and in the adult (6). Grb10 paternal expression seems to be exclusive to neurons while being excluded from glia in adult tissues, and Grb10 expression in primary glial cultures and cell lines has been previously described as exclusively maternal (50).…”

“…Notably, Grb10 overexpression is linked to severe pancreatic dysfunction and dysmorphia in juvenile mice (36). Reduction in Grb10 expression is associated with widespread neonatal and postnatal overgrowth, along with increased sensitivity to insulin (6,34,37,38). Pancreas-specific Grb10 deletion results in increased insulin production and improved glucose tolerance (39).…”

“…These expression patterns are established by midembryonic development and are largely maintained in the adult. In the adult mouse brain, Grb10 paternal expression is evident within thalamic, hypothalamic, midbrain, hindbrain, and forebrain nuclei (6). Of note, nearly all monoaminergic cell populations within the midbrain and hindbrain show paternal Grb10 expression (6).…”

“…The first characterized Grb10 knockout mouse exhibited overgrowth in numerous organs and tissues, suggesting that Grb10 acts as a potent growth suppressor in vivo (5). Other Grb10 knockout mouse models have additionally shown that Grb10 plays an important role in social dominance behavior in mice (6).…”

Evolution of genomic imprinting as a coordinator of coadapted gene expression

“…First, imprinted genes tend to have a clustered distribution in mammalian (15,18,19) and plant genomes (20), with the mammalian clustering appearing to be conserved in vertebrate evolution (21). Second, imprinted genes appear to modulate a limited number of types of traits, with most genes having effects on growth (especially in relation to the demand for maternal provisioning, often via the placenta) and/or behaviors (17,22), with behavioral effects being largely associated with parental and social behaviors (13,(23)(24)(25)(26)(27). Many of the theories for the evolution of genomic imprinting arise from or are strongly tied to this apparently limited range of phenotypes influenced by most imprinted genes.…”