Maternal HtrA3 optimizes placental development to influence offspring birth weight and subsequent white fat gain in adulthood

Ying Li,Jonathan Hyett,Guiying Nie,Fabricio Da Silva Costa,Lois Salamonsen

doi:10.1016/j.placenta.2017.07.208

Abstract

High temperature requirement factor A3 (HtrA3), a member of the HtrA protease family, is highly expressed in the developing placenta, including the maternal decidual cells in both mice and humans. In this study we deleted the HtrA3 gene in the mouse and crossed females carrying zero, one, or two HtrA3-expressing alleles with HtrA3+/- males to investigate the role of maternal vs fetal HtrA3 in placentation. Although HtrA3-/- mice were phenotypically normal and fertile, HtrA3 deletion in the mother resulted in intra-uterine growth restriction (IUGR). Disorganization of labyrinthine fetal capillaries was the major placental defect when HtrA3 was absent. The IUGR caused by maternal HtrA3 deletion, albeit being mild, significantly altered offspring growth trajectory long after birth. By 8 months of age, mice born to HtrA3-deficient mothers, independent of their own genotype, were significantly heavier and contained a larger mass of white fat. We further demonstrated that in women serum levels of HtrA3 during early pregnancy were significantly lower in IUGR pregnancies, establishing an association between lower HtrA3 levels and placental insufficiency in the human. This study thus revealed the importance of maternal HtrA3 in optimizing placental development and its long-term impact on the offspring well beyond in utero growth.

Highlights

High-temperature requirement factor A (HtrA) proteins are a family of serine proteases with functional importance in regulating protein-protein interactions and protein folding stress[1]
(27760 bp, located on chromosome 5) is schematically illustrated in Supplementary Figure 1A. It contains 10 exons; alternative splicing leads to two High temperature requirement factor A3 (HtrA3) mRNA transcripts (L-mRNA and S-mRNA), which translate into two protein isoforms (L-Protein, 459; S-Protein, 363aa)[5]
Exons 1–6 are transcribed into both HtrA3 mRNA transcripts, whereas exons 8, 9 and 10 are specific to the long and exon 7 is unique to the short HtrA3 mRNA transcript[5] (Supplementary Figure 1A)

Summary

Introduction

High-temperature requirement factor A (HtrA) proteins are a family of serine proteases with functional importance in regulating protein-protein interactions and protein folding stress[1]. HtrA3 was initially cloned, in both the mouse and human, from the developing placenta because of high HtrA3 expression[5, 6, 25, 26]. The maternal decidual cells within the decidua basalis strongly express HtrA3, and the level is highest during early pregnancy when the placenta is actively developing[26]. HtrA3 is highly expressed in maternal decidual cells during human placental development[25]. HtrA3 is expressed by a number of trophoblast subtypes including the villous syncytiotrophoblast, during the first trimester of pregnancy[25]. A recent study identified HtrA3 as a potential target of a prolactin family paralog in maternal decidual cells during mouse placental development[32]. To date, the functional importance of HtrA3 in placental development and function is unknown

Methods

Results

Conclusion