Genomic imprinting and neurobehavioral programming by adverse early life environments: evidence from studying Cdkn1c

Abstract

Imprinted genes are subject to epigenetic regulation that leads to monoallelic expression from one parental allele only. Brain expression of the imprinted gene Cdkn1c is sensitive to early life adversity, including exposure to maternal low protein diet (LPD) where increased expression of Cdkn1c is due to de-repression of the normally silent paternal allele. Maternal LPD also leads to changes in the dopamine system and reward related behaviours in offspring. We have recently demonstrated that these brain and behavioural phenotypes are recapitulated in a transgenic model in which Cdkn1c expression alone is increased. Here we summarise these findings and suggest that the loss of imprinting of Cdkn1c in the offspring following maternal low protein diet is a key contributor to the associated changes in the dopamine system and behavior reported after early life adversity.

Protein restriction during pregnancy alters Cdkn1c silencing, dopamine circuitry and behaviour in offspring without wholescale disruption of neuronal gene expression

“…Supplementation of maternal LPD with folate as a source of methyl-donors, corrects methylation across the sDMR and substantially reduces Cdkn1c misexpression in the resulting offspring [28]. These results show some similarity to prior genetic experiments where relatively mild over-expression of Cdkn1c was shown to be su cient to provoke increased numbers of TH-positive cells in the periventricular hypothalamus and VTA, and a range of behavioural abnormalities that included altered reward-related and social dominance behaviours [20,21,22,29]. Taken together, these studies support a fundamental role for Cdkn1c in the developing brain, where mild mis-expression has long-term consequences for the development and ne-tuning of neural stem and progenitor populations and the dopamine circuitry that ensues.…”

“…Elevated numbers of midbrain TH-positive neurons in offspring exposed in utero to LPD De-repression of paternal Cdkn1c-Fluc-lacZ initiated early in gestation can continue beyond birth and long after LPD exposure, whilst gestational sensitivity to LPD is ameliorated by supplementation of maternal LPD with folate, which effectively restores correct DNA methylation across the sDMR [28]. Independent studies by others have also shown that folate depletion in pregnancy impacts brain development in adults [27,31,34] and that Cdkn1c upregulation can alter the proliferation and differentiation of developing dopaminergic neurons within the midbrain [20,27,29]. We therefore examined the brains and the behaviours of juvenile and adult offspring that had experienced gestational LPD exposure.…”

“…Dopaminergic cells in the midbrain are involved in movement regulation and pharmacological stimulation of the dopamine system results in increased extracellular dopamine concentration and hyperactivity in rodents [39]. Overexpression of Cdkn1c can alter dopamine circuitry in mice [20,27,29] and has been associated with hyperactivity in humans [40]. To explore this, we examined the responses of CD-or LPD-exposed offspring to cocaine.…”

“…Although the exact timing of this sensitivity to dietary challenge remains uncertain, monoallelic Cdkn1c expression is evident in mouse embryos from E6.5 onwards [30], while pre-implantation exposure (E3.5) to low protein diet is reported to be su cient to trigger a permanent reduction in neural stem cell numbers in the foetal brain [31], as well as reducing bone growth at later gestational stages [32]. Early life exposure to low protein diet has also been linked to altered behaviour [29,33], including changes in dopamine-dependent reward-processing and locomotor activity [27]. To longitudinally monitor allelic Cdkn1c expression in vivo, we previously developed a novel mouse reporter where imprinted gene expression can be visualised by bioluminescence imaging [28].…”

“…Exposure to diets that are low in protein during pregnancy is known to enhance Cdkn1c expression in embryos, eroding DNA methylation across important regulatory regions, such as the somatic differentially methylated region (sDMR) of the locus [27,28,29]. Although the exact timing of this sensitivity to dietary challenge remains uncertain, monoallelic Cdkn1c expression is evident in mouse embryos from E6.5 onwards [30], while pre-implantation exposure (E3.5) to low protein diet is reported to be su cient to trigger a permanent reduction in neural stem cell numbers in the foetal brain [31], as well as reducing bone growth at later gestational stages [32].…”