Christopher Gregg and Catherine Dulac
Parents influence the brain development and the behavior of their offspring in extraordinary and varied ways that impact the success of their offspring in life and susceptibility to neurological disorders and disease. These influences are typically considered from the perspectives of genetic inheritance and the impact of parental behaviors. However, maternally and paternally inherited chromosomes are not functionally equivalent, due to heritable epigenetic marks established in the parental gametes, called genomic imprints. David Haig (Harvard University, Department of OEB) has proposed the Kinship Theory for the evolution of imprinting, which suggests that the phenomenon of genomic imprinting in mammals results from an evolutionary conflict between mothers and fathers over the expression of specific physiological and behavioral traits in offspring. The theory postulates that maternally expressed genes act antagonistically to the functions of paternally expressed genes, mainly over the sharing of maternal resources. Imprinting is thought to be rare in the genome, affecting ~100 genes in mice, and yet examples of transgenerational effects on gene expression, brain function and the behavior of offspring are growing and increasingly mysterious. Experiments in which chimeric mice were generated from a mix of wildtype cells and parthenogenetic (PG) or androgenetic (AG) cells revealed preferential contribution of cells with a maternally-derived genome (PG cells) to cortical and limbic brain regions, but cells with a paternally-derived genome (AG cells) contributed strictly to hypothalamic regions (1). From these findings, it was proposed that mothers and fathers differentially influence the evolution and function of the cortex versus hypothalamus, respectively. However, these findings have not been confirmed, and the nature of maternal and paternal gene expression programs in the brain is largely unknown.
Our study was performed as a collaboration with David Haig, Jiangwen Zhang in Harvard University, FAS Research Computing, and Shujun Luo and Gary Schroth at Illumina Inc.. We performed RNA-Seq on specific brain regions of F1 hybrid offspring generated by reciprocal crosses of CASTEiJ and C57BL/6J mice and distinguished expression levels from maternally versus paternally inherited alleles using the SNP sites. Inspired by the chimera studies that suggested preferential maternal control over cortical regions and preferential paternal control over hypothalamic regions, we compared parent specific gene expression programs in the adult medial prefrontal cortex (mPFC) and the preoptic area (POA) of the hypothalamus. The number of genes subject to parental effects in these regions is greater than expected (~372 genes) and involves complex isoform-specific parental effects. However, we did not find evidence for biased maternal control over the cortex. Instead, we found that in both the mPFC and POA, ~70% of autosomal genes exhibiting parental effects preferentially express the paternal allele (figure, panel A). Interestingly, an analysis of X-linked gene expression in females revealed preferential expression of the maternally-inherited X in regions of the adult female brain and this was confirmed with a transgenic approach. In males, the X is strictly maternally derived. We speculate that the autosomes and X chromosome give rise to paternal and maternal gene expression programs, respectively, which influence adult brain function and behavior.
Parental effects in the developing brain differed from those found in the adult. We found ~553 genes subject to parental effects in the embryonic day 15 (E15) brain, compared to 257 in the adult POA and 153 in the adult mPFC. Further, rather than a paternal expression bias, 61% of the genes in the developing brain exhibited preferential expression of the maternal allele. These results reveal maternal effects that are specifically associated with brain development. Finally, we analyzed males and females separately and uncovered evidence for sex specific parental effects in the brain. In the POA of the hypothalamus, we noted that females have 3 times the number of genes subject to sex specific parental effects as males. The POA plays a central role in regulating maternal behavior. Given that maternal behavior alone impacts offspring brain development and behavior, this result suggests a remarkable convergence of parental influences.
Our studies of parent-specific gene expression programs in the brain suggest surprising and complex modes of parental influence over brain development and function in offspring. What are the mechanisms that regulate these effects? How are maternal and paternal gene expression programs functionally related? Do parental influences on gene expression adapt to environmental pressures? How do these parental effects influence the behavior and physiology of offspring? What is the nature of parental effects in humans? These questions set a course for an exciting frontier and may shed new lights on our understanding of brain evolution, function and disease. 1. E. B. Keverne, Prog Brain Res 133, 279 (2001)
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