Fetal Brain Elicits Sexually Conflicting Transcriptional Response to the Ablation of Uterine Forkhead Box A2 (Foxa2) in Mice

Abstract

In this study, we investigated the effects of ablation of uterine Forkhead Box A2 (Foxa2) on gene expression of fetal brain relative to placenta. Using a conditional knockout mouse model for uterine Foxa2, here we show that the lack of uterine Foxa2 elicits a sexually-conflicting transcriptional response in the fetal brain relative to placenta. The ablation of Foxa2 in the uterus altered expression of genes related to growth, nutrient sensing, aging, longevity and angiogenesis among others. In the wildtype mice, these genes were expressed higher in the fetal brain and placenta of males compared to females. However, in mice lacking uterine Foxa2, the same genes showed the opposite pattern i.e., higher expression in the fetal brain and placenta of females compared to males. Based on the known marker genes of mice placenta and fetal brain cells, we further predicted that the genes exhibiting the sexually conflicting expression were associated with vascular endothelial cells. Overall, our study suggests that uterine Foxa2 plays a role in the regulation of the brain-placental axis by influencing the fetoplacental vascular changes during pregnancy.

Fetal origin of sex‐bias brain aging

“…RNA‐seq data analysis was performed as described in our earlier studies 41,42 . Briefly, the quality of raw sequences was checked with FastQC followed by trimming the adaptors from the sequence reads by cutadapt .…”

Fetal origin of sex-bias brain aging

“…Our earlier study showed a coordinated changes of specific receptor and ligand genes between the placenta and fetal brain, suggesting their roles in the regulation of the brain-placental axis in mice (36). In addition, we also found evidences for differential expression of specific aging genes in the male and female fetal brain in response to ablation of uterine Foxa2 , an essential gene required for pregnancy establishment (37). We also showed that specific genes are regulated in a sex-bias manner during fetal brain development in pigs (38).…”

“…The RNA-seq data of brain and placenta from male and female fetuses (GD15) was compared with RNA-seq data of PND5 and WK70 brain. The GD15 RNA-seq data was generated earlier by us (37) which are also publicly available in the Gene Expression Omnibus database (accession # GSE157555). Total RNA was isolated from PND5 and WK70 brain samples using TRIzol (Catalog 15596026, Thermo Fisher) based protocol.…”

“…RNA-seq data analysis was performed as described in our earlier studies (37, 38). Briefly, the quality of raw sequences was checked with FastQC followed by trimming the adaptors from the sequence reads by cutadapt .…”

“…We also showed that specific genes are regulated in a sex-bias manner during fetal brain development in pigs (38). Furthermore, studies by others have shown that epigenetic and metabolic changes in the fetal brain can impact overall health later in life (34, 35) particularly in the context of declining metabolism in the brain (36, 37). However, the epigenetic connection between development and aging of brain remains poorly studied.…”