Evidence for functional interactions between the placenta and brain in pregnant mice

Abstract

The placenta plays a pivotal role in the development of the fetal brain and also influences maternal brain function, but our understanding of communication between the placenta and brain remains limited. Using a gene expression and network analysis approach, we provide evidence that the placenta transcriptome is tightly interconnected with the maternal brain and fetal brain in d 15 pregnant C57BL/6J mice. Activation of serotonergic synapse signaling and inhibition of neurotrophin signaling were identified as potential mediators of crosstalk between the placenta and maternal brain and fetal brain, respectively. Genes encoding specific receptors and ligands were predicted to affect functional interactions between the placenta and brain. Paralogous genes, such as sex comb on midleg homolog 1/scm‐like with 4 mbt domains 2 and polycomb group ring finger (Pcgf) 2/Pcgf5, displayed antagonistic regulation between the placenta and brain. Additionally, conditional ablation of forkhead box a2 (Foxa2) in the glands of the uterus altered the transcriptome of the d 15 placenta, which provides novel evidence of crosstalk between the uterine glands and placenta. Furthermore, expression of cathepsin 6 and monocyte to macrophage differentiation associated 2 was significantly different in the fetal brain of Foxa2 conditional knockout mice compared with control mice. These findings provide a better understanding of the intricacies of uterus‐placenta‐brain interactions during pregnancy and provide a foundation and model system for their exploration.—Behura, S. K., Kelleher, A. M., Spencer, T. E. Evidence for functional interactions between the placenta and brain in pregnant mice. FASEB J. 33, 4261–4272 (2019). http://www.fasebj.org

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

“…In women, altered or failed endometrial decidualization is an essential contributor to later pregnancy complications, such as preeclampsia and pregnancy loss (13), and may be involved in fetal growth restriction and preterm labor (56)(57)(58). Recent evidence supports the idea that GE-derived factors regulate stromal cell decidualization and placental growth in mice (2,59) and humans (8)(9)(10)60). In the present study, we identified many potential FOXA2-regulated genes in the MS phase that encode secreted ligands with receptors on decidualized stromal cells.…”

Regulation of uterine genes during the peri‐implantation period, and its relationship to the maternal brain in gestating mice

“…The gene expression of the GD4 maternal brain (MB4) from the present study was compared with the gene expression data of the GD15 maternal brain (MB15) from our previous study (Behura, Kelleher et al, 2019). From this comparison based on the edgeR‐robust analysis (Zhou, Lindsay, & Robinson, 2014), we identified a total of 3,066 genes that showed significant changes (false discovery rate [FDR] p < .05) in expression level in MB15 compared with MB4 (Figure 3).…”

“…The neuroendocrine signaling modulates the maternal–fetal communication, development of the placenta and fetus, and the timing of parturition (Brüning et al, 2000; Mastorakos & Ilias, 2003). These processes are influenced by hormonal interaction between the brain and reproductive organs (Barth, Villringer, & Sacher, 2015; Behura, Dhakal et al, 2019; Behura, Kelleher, & Spencer, 2019; Christensen et al, 2012; Gorski, 1979). The maternal brain (MB) regulates the production of estrogen, progesterone, prolactin, and oxytocin that play important roles in pregnancy (Hillerer, Jacobs, Fischer, & Aigner, 2014; Kim & Strathearn, 2016).…”

“…Over the next week, the placenta develops in the mesometrial area of the uterus and is fully formed and functional by GD15 (Watson & Cross, 2005). On this day, the placenta expresses genes in a correlated manner with the maternal as well as the fetal brain (Behura, Kelleher et al, 2019). Foxa2 that plays a major role in endometrial gland development (Jeong et al, 2010; Kelleher, Milano‐Foster, Behura, & Spencer, 2018; Kelleher et al, 2017) also influences placental function as its ablation in the uterus leads to dysregulated placenta transcriptome (Behura, Kelleher et al, 2019).…”

“…On this day, the placenta expresses genes in a correlated manner with the maternal as well as the fetal brain (Behura, Kelleher et al, 2019). Foxa2 that plays a major role in endometrial gland development (Jeong et al, 2010; Kelleher, Milano‐Foster, Behura, & Spencer, 2018; Kelleher et al, 2017) also influences placental function as its ablation in the uterus leads to dysregulated placenta transcriptome (Behura, Kelleher et al, 2019). Though the role of the brain–placental axis in pregnancy is known (Behura, Dhakal et al, 2019), the communication between the brain and the uterus during the peri‐implantation period has not been investigated.…”