Essays on Science and SocietyEPPENDORF WINNER

Parental Control over the Brain

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Science  05 Nov 2010:
Vol. 330, Issue 6005, pp. 770-771
DOI: 10.1126/science.1199054

Parents influence our brain development and behavior so substantially that they can set us on a course for life. Often we consider the impact of parenting styles or genetics in this context. However, maternally and paternally inherited chromosomes are not functionally equivalent, due to heritable epigenetic marks established in the parental gametes, called genomic imprints. 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. In one set of experiments, chimeric mice were generated by aggregating wild-type cells and cells containing either only maternal (parthenogenetic, PG) or paternal (androgenetic, AG) chromosomes. PG cells contributed preferentially to cortical and limbic brain regions, while AG cells contributed only to hypothalamic regions (1). From these findings, it was proposed that mothers and fathers preferentially influence the evolution and function of the cortex and hypothalamus, respectively. Several other parental effects have also been uncovered (2). In a study of genetically identical uniparental mice, a complex paternal transmission pattern of anxiety-related behaviors and growth effects was found that suggests epigenetic and sex-specific transgenerational effects (3). Similarly complex effects have been described in humans (4).

Maternal and paternal gene expression programs in the brain.

(A) Numbers of maternally expressed genes (MEGs) and paternally expressed genes (PEGs) in the adult and developing brain. (B) Preferential expression of the maternally inherited X (Xm) in the female mPFC revealed by crosses of an X-linked egfp reporter mouse to wild-type mice. (C) RNA-Seq analysis reveals preferential expression of the interleukin-18 (Il-18) maternal allele (red) relative to the paternal allele (blue) in the female, but not male, mPFC (F1i, mouse strain CASTEiJ mother crossed with a C57BL/6J father; F1r, CASTEiJ father crossed with a C57BL/6J mother). (D) Quantitative polymerase chain reaction analysis of Il-18 expression in maternal versus paternal deletion Il-18 heterozygous mice reveals reduced expression in the mPFC of female, but not male, maternal deletion mice relative to paternal deletion mice.

Parental effects have been clearly linked to human brain function and behavior through studies of Prader-Willi syndrome (PWS) and Angelmen syndrome (AS), which result from a paternally or maternally inherited deletion of an imprinted gene cluster on chromosome 15, respectively. PWS is associated with hyperphagia, stubbornness, and compulsive traits (5), whereas AS is associated with absence of speech, a happy demeanor, and inappropriate laughter (6). Taken together, these studies highlight the potential for parental effects to influence the behavior and physiology of offspring, and suggest an underlying biology and epigenetic mode of inheritance that are clearly important but poorly understood.

My studies, with collaborators at Harvard, are focused on understanding the differences and functions of paternal and maternal gene expression programs in the developing and adult brain (7, 8). We initially mapped the expression pattern of 45 known imprinted genes across 118 adult brain regions. This study identified neural systems that are enriched for the expression of imprinted genes. We found the major monoaminergic nuclei of the brain (regions with serotonergic, dopaminergic, or noradrenergic neurons), as well as nuclei involved in feeding behavior, such as the arcuate nucleus, and social behavior, such as the preoptic area, to be enriched for imprinted gene expression. These initial observations prompted us to develop a genome-wide approach to study parental effects in specific brain regions at different developmental stages.

We first performed RNA-Seq analysis, a transcriptome profiling approach that uses deep-sequencing technologies, on cDNA libraries from two distantly related mouse strains, CASTEiJ and C57BL/6J, to identify all coding single-nucleotide polymorphisms (SNPs) that distinguish the two strains. We then performed RNA-Seq on specific brain regions of F1 hybrid offspring generated by reciprocal crosses of CASTEiJ and C57BL/6J mice and used the SNP sites to distinguish expression levels from maternally versus paternally inherited alleles. 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 was greater than expected (∼372 genes) and involved 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 expressed 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 (figure, panel B). In males, the X is strictly maternally derived. Previous work revealed that the X chromosome has evolved a preferential role in the regulation of the brain (9). 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, as compared to 257 in the adult POA and 153 in the adult mPFC (figure, panel A). 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. An important example is interleukin-18 (Il-18), which exhibits preferential expression in the female, but not male, mPFC (figure, panels C and D). Il-18 has been linked to multiple sclerosis (10), a sexually dimorphic neurological disease that predominates in women and is associated with maternal parent-of-origin effects (11). In the POA of the hypothalamus, we also noted that females have three 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 affects offspring brain development and behavior, this result suggests a remarkable convergence of parental influences.

Our studies of parent-specific gene expression programs in the central nervous system 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 light on our understanding of brain evolution, function, and disease.

  • Eppendorf and Science are pleased to present the prize-winning essay by Christopher Gregg, the 2010 winner of the Eppendorf and Science Prize for Neurobiology.

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