Placental protection of the fetal brain during short-term food deprivation

Abstract

The fetal genome regulates maternal physiology and behavior via its placenta, which produces hormones that act on the maternal hypothalamus. At the same time, the fetus itself develops a hypothalamus. In this study we show that many of the genes that regulate placental development also regulate the developing hypothalamus, and in mouse the coexpression of these genes is particularly high on embryonic days 12 and 13 (days E12-13). Such synchronized expression is regulated, in part, by the maternally imprinted gene, paternally expressed gene 3 (Peg3), which also is developmentally coexpressed in the hypothalamus and placenta at days E12-13. We further show that challenging this genomic linkage of hypothalamus and placenta with 24-h food deprivation results in disruption to coexpressed genes, primarily by affecting placental gene expression. Food deprivation also produces a significant decrease in Peg3 gene expression in the placenta, with consequences similar to many of the placental gene changes induced by Peg3 mutation. Such genomic dysregulation does not occur in the hypothalamus, where Peg3 expression increases with food deprivation. Thus, changes in gene expression brought about by food deprivation are consistent with the fetal genome's maintaining hypothalamic development at a cost to its placenta. This biased change to gene dysregulation in the placenta is linked to autophagy and ribosomal turnover, which sustain, in the short term, nutrient supply for the developing hypothalamus. Thus, the fetus controls its own destiny in times of acute starvation by short-term sacrifice of the placenta to preserve brain development.

Fig. 1.

(A) Changes in gene expression in the developing placenta and hypothalamus show increasing synchronization for expression in these tissues over days E11–13. (B) Peg3 inactivation particularly targets coexpressed genes, suppressing some and activating others; 24-h starvation virtually eliminates hypothalamus/placental coexpression, particularly targeting the placenta at a level fourfold that of the placenta.

Fig. 2.

Pathway analysis. The functionally defined pathways activated by 24 h of maternal food deprivation alone (Upper) and those activated by changes in gene expression that are common to Peg3 inactivation and 24 h of maternal food deprivation (Lower).