Abstract
The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1c BACx1) with a twofold elevation in Cdkn1c expression that mimics loss‐of‐imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1c BACX1 mice displayed altered expression of dopamine system‐related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1c BACx1 animals were hypersensitive to amphetamine as showed by c‐fos expression in the nucleus accumbens. Cdkn1c BACX1 mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1c BACX1 mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine‐related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour.
Highlights
Imprinted genes represent a class of genes that are monoallelically expressed, allelic expression being dependant on the parent of origin, as a result of epigenetic events initiated in the germline (Ferguson-Smith 2011)
There was no significant change in the Dopamine transporter (Dat) mRNA in the ventral striatum [t(5) = 1.5, P = 0.19] of Cdkn1cBACx1 animals compared with WT littermates
In the dorsal striatum there was a ninefold increase in Dat mRNA [Fig. 1c; t(5) = 4.696, P = 0.005] in the dorsal striatum, this was accompanied by a 20% increase in whole tissue level of dopamine in the dorsal striatum of Cdkn1cBACx1 animals [Fig. 1d; t(14) = −2.298, P = 0.038], without a change in the metabolite DOPAC [t(14) = −0.323, P = 0.75] or in turnover [t(14) = 0.874, P = 0.397, data not shown]
Summary
Imprinted genes represent a class of genes that are monoallelically expressed, allelic expression being dependant on the parent of origin, as a result of epigenetic events initiated in the germline (Ferguson-Smith 2011) This class of genes were identified following on from the observation of the non-equivalence of the parental genomes in androgenetic, gynogenetic and parthenogenetic murine embryos resulting in embryonic fatality (McGrath & Solter 1984; Surani et al 1984). Corresponding to this, changes in a number of behaviours, motivation for a food reward and social dominance, were observed These findings lend further support to the importance of genomic imprinting in mediating complex mammalian behaviours and emphasize the significance of Cdkn1c expression for dopaminergic system function
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