Neurogenesis Potential Evaluation and Transcriptome Analysis of Fetal Hypothalamic Neural Stem/Progenitor Cells With Prenatal High Estradiol Exposure.

Huihui Wang,Min Hou,Hefeng Huang,Chengliang Zhou,Yun Sun

doi:10.3389/fgene.2021.677935

Abstract

High maternal estradiol is reported to induce metabolic disorders by modulating hypothalamic gene expression in offspring. Since neurogenesis plays a crucial role during hypothalamus development, we explored whether prenatal high estradiol exposure (HE) affects proliferation and differentiation of fetal hypothalamic neural stem/progenitor cells (NSC/NPCs) in mice and performed RNA sequencing to identify the critical genes involved. NSC/NPCs in HE mice presented attenuated cell proliferation but increased neuronal differentiation in vitro compared with control (NC) cells. Gene set enrichment analysis of mRNA profiles indicated that genes downregulated in HE NSC/NPCs were enriched in neurogenesis-related Gene Ontology (GO) terms, while genes upregulated in HE NSC/NPCs were enriched in response to estradiol. Protein-protein interaction analysis of genes with core enrichment in GO terms of neurogenesis and response to estradiol identified 10 Hub mRNAs, among which three were potentially correlated with six differentially expressed (DE) lncRNAs based on lncRNA profiling and co-expression analysis. These findings offer important insights into developmental modifications in hypothalamic NSC/NPCs and may provide new clues for further investigation on maternal environment programmed neural development disorders.

Highlights

The theory that the intrauterine environment can influence prenatal development and the future health of offspring (Bateson et al, 2004) has resulted in increased interest in the developmental origin of chronic disease
Because a prenatally programmed adult hypothalamic disorder resulting from high maternal estradiol has been identified (Wang et al, 2018), here we explore whether neurogenesis potential is affected in fetal hypothalamic NSC/NPCs and attempt to identify the key lncRNA-mRNA network through integrated bioinformatic analysis
The results revealed that genes downregulated in high estradiol exposure (HE) NSC/NPCs were enriched in neurogenesis-related Gene Ontology (GO) biological processes (BP), such as neuroblast division, neuroblast proliferation, stem cell division, and neuron fate commitment, while genes upregulated in HE NSC/NPCs were enriched in response to estradiol (Figure 2D)

Summary

Introduction

The theory that the intrauterine environment can influence prenatal development and the future health of offspring (Bateson et al, 2004) has resulted in increased interest in the developmental origin of chronic disease. Our previous study reported a programming effect by high maternal estradiol during early pregnancy on the hypothalamic glucoregulatory system of male mouse offspring, which induces adult metabolic disorders (Wang et al, 2018). This discovery indicates that high prenatal estradiol levels alter hypothalamus development, though the underlying mechanism is not yet well understood. NSC/NPCs are preprogrammed to form specific types of functional neurons even before birth (Fuentealba et al, 2015); the study of prenatal neurogenesis may help researchers understand the mechanisms underlying adult neural disorders

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