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

Pramod Dhakal,Monica Strawn,Susanta K Behura,Ananya Samal

doi:10.3390/ijms22189693

Pramod Dhakal, Monica Strawn + Show 2 more

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https://doi.org/10.3390/ijms22189693

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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.

Highlights

The Forkhead box A2 (Foxa2) is a major transcription factor that plays diverse roles in reproduction, development and human diseases [1]
The current study addresses the questions as to whether a uterus lacking Foxa2 has an influence on the transcriptional response of the fetal brain, and whether that influence is conditioned by the fetal sex and placenta
The weights of male and female fetuses and their corresponding placentae of the wildtype (WT) and conditional knockout mice were measured on the gestation day 15 (GD15) (Figure 1A)

Summary

Introduction

The Forkhead box A2 (Foxa2) is a major transcription factor that plays diverse roles in reproduction, development and human diseases [1]. The role of Foxa in uterine gland development and pregnancy establishment has been studied [6]. Mice lacking uterine Foxa are infertile, but pregnancy can be rescued by injection of leukemia inhibitory factor (LIF) [8,9]. LIF is expressed in the uterus in response to estrogen from the ovary, and requires the transcription factor Foxa for blastocyst implantation [6,7]. The conditional knockout of Foxa in the uterus alters gene expression of the placenta [10]. There is remarkable coordination in the gene expression between the placenta and fetal brain, suggesting a functional interaction between the brain and placenta (aka the brain-placental axis) [10]. The brain-placental axis, is vulnerable to intrauterine conditions that influence pregnancy outcomes [11]

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