Placental effects on maternal brain revealed by disrupted placental gene expression in mouse hybrids

Abstract

The mammalian placenta is both the physical interface between mother and fetus, and the source of endocrine signals that target the maternal hypothalamus, priming females for parturition, lactation and motherhood. Despite the importance of this connection, the effects of altered placental signaling on the maternal brain are understudied. Here, we show that placental dysfunction alters gene expression in the maternal brain, with the potential to affect maternal behavior. Using a cross between the house mouse and the Algerian mouse in which hybrid placental development is abnormal, we sequenced late gestation placental and maternal medial preoptic area transcriptomes and quantified differential expression and placenta-maternal brain co-expression between normal and hybrid pregnancies. The expression of Fmn1, Drd3, Caln1 and Ctsr was significantly altered in the brains of females exposed to hybrid placentas. Most strikingly, expression patterns of placenta-specific gene families and Drd3 in the brains of house mouse females carrying hybrid litters matched those of female Algerian mice, the paternal species in the cross. Our results indicate that the paternally-derived placental genome can influence the expression of maternal-fetal communication genes, including placental hormones, suggesting an effect of the offspring’s father on the mother’s brain.

Placental genotype affects early postpartum maternal behaviour

“…To our knowledge, the effects of altered placental expression on wild-type female mice have been tested for only three imprinted genes: Peg3 , Grb10 and Phlda2 [25,26,28,30]. In the hybrid system studied here, Grb10 and Phlda2 are among the 13 imprinted genes with significantly altered expression in hybrid relative to M. m. domesticus placenta [34]. Specifically, Grb10 is upregulated in hybrid placenta relative to M. m. domesticus and Phlda2 is overexpressed relative to both parental species [34].…”

“…In the hybrid system studied here, Grb10 and Phlda2 are among the 13 imprinted genes with significantly altered expression in hybrid relative to M. m. domesticus placenta [34]. Specifically, Grb10 is upregulated in hybrid placenta relative to M. m. domesticus and Phlda2 is overexpressed relative to both parental species [34]. Whereas placental Grb10 influences maternal metabolism and nutrient transfer [28], phenotypes not measured here, Phlda2 negatively regulates placental endocrine cell lineages and has distinct effects on postnatal maternal behaviour up to 4 days postpartum when over- versus under-expressed [29,30].…”

“…Additionally, overexpression of Phlda2 decreases the size of the endocrine compartment of the placenta [29]. Fourth, female M. m. domesticus carrying near-term hybrid litters have altered expression in the hypothalamus relative to conspecific mothers of normal litters [34]. In particular, Drd3 , a dopamine receptor associated with treatment-resistant major depression in humans [41] and anxiety- and depressive-like behaviours in a laboratory mouse knockout [42], is downregulated in the maternal brain in hybrid pregnancies [34].…”

Haldane’s rule in the placenta: sex-biased misregulation of theKcnq1imprinting cluster in hybrid mice

“…146 Placentas used for histology were fresh frozen and stored at -80°C until cryosectioning. Transcriptome data processing and analysis 163 QC, trimming of raw sequencing reads, filtering and mapping were performed as described 164 (Arévalo and Campbell 2020). To improve comparability, all samples (Dom, Spret and hybrid) 165 were mapped to a pseudo-hybrid genome, generated using the genome preparation tool of the 166 program SNPsplit (Krueger and Andrews 2016 Spret were then N-masked to allow mapping of both Dom-and Spret-derived reads.…”

“…However, 590 the immediate consequences of an adverse intrauterine environment are generally more severe in 591 males, with more pronounced placental pathology and intrauterine growth restriction, and a 592 higher rate of mortality for male fetuses (Cooperstock and Campbell 1996;Walker et al 2012;593 Sandman et al 2013;Davis and Pfaff 2014). Female M. m. domesticus carrying hybrid litters are 594 potentially exposed to altered placental endocrine signaling due to deficits in spongiotrophoblast 595 cells in hybrid placentas (Zechner et al 1996), and exhibit altered neural gene expression at 596 e17.5 (Arévalo and Campbell 2020) and reduced maternal behavior immediately postpartum 597 (Gardner et al 2019). These observations suggest that hybrid pregnancy disrupts maternal 598 homeostasis and, in this sense, is a physiological stressor.…”