Homeobox genes and down-stream transcription factor PPARγ in normal and pathological human placental development

Abstract

The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface is controlled by nuclear transcription factors including homeobox genes. Here we summarize current knowledge regarding the expression and function of homeobox genes in the placenta. We also describe the identification of target transcription factors including PPARγ, biological pathways regulated by homeobox genes and their role in placental development. The role of the nuclear receptor PPARγ, ligands and target genes in human placental development is also discussed. A better understanding of these pathways will improve our knowledge of placental cell biology and has the potential to reveal new molecular targets for the early detection and diagnosis of pregnancy complications including human fetal growth restriction.

Introduction

During pregnancy, the placenta orchestrates multiple functions, which are required to initiate, maintain and control the outcome of gestation. In particular, generation of distinct trophoblast cell types within the placenta is required to fulfill the complex biological processes of implantation, maternal–fetal exchange and maternal tolerance of fetal–parental antigens. In some species, including human, the placenta performs hormonal functions required for the maintenance of gestation and fetal development.

Trophoblasts originate from the trophectoderm, the outermost epithelial cell layer of the blastocyst, which triggers attachment and implantation in the receptive endometrium of the mother. In humans, the principal structures of the haemochorial placenta are apparent as early as the 21st day of pregnancy [1], [2]. Following blastocyst adhesion, trophoblast cells proliferate rapidly and undergo cell fusion to form the syncytium. By day 21 after ovulation, in the human, the chorionic villi, the definitive structural and functional units of the placenta, become established.

The trophoblast differentiates into either the villous (VCT) or the extravillous trophoblast (EVT) lineages. In the villous lineage, the cytotrophoblasts of the floating villi, which are present in the intervillous space, remain attached to the villous basement membrane and form a monolayer of epithelial cells. These cells proliferate and differentiate by fusion to form the syncytium, which covers the entire surface of the villus. Thus, the multinucleated syncytium of the definitive placenta is generated by continuous fusion of underlying mononuclear VCT. The syncytium is multi-functional, with primary functions that include absorption, exchange and transport of nutrients and gases from the maternal to the fetal circulation, and specific hormonal functions. Additionally, the multinuclear syncytium is the primary site of major endocrine activity of the organ since it secretes hormones such as human chorionic gonadotropin (hCG), human placental lactogen (hPL) or placental growth hormone (PGH), which are important for placental growth and/or maternal adaptation to pregnancy [3], [4], [5].

In the EVT phenotype, the cytotrophoblast cells at the tip of the anchoring villi proliferate, and subsequently differentiate to form multicellular columns of cells that invade into maternal decidua and into the first third of the myometrium. Interstitial trophoblasts invade the decidua and parts of the myometrium, whilst endovascular trophoblasts migrate and invade along the wall of the uterine spiral arteries, which results in remodeling of the uterine spiral arteries [6]. In particular, modification of the maternal vessels by trophoblasts, which replace the maternal endothelium, is thought to be critical for the successful progression of pregnancy since absence of the endovascular trophoblasts is associated with cases of preeclampsia (PE) and fetal growth restriction (FGR) [7], [8]. Thus, it is evident that elucidation of the key molecular mechanisms controlling commitment and regulating differentiation of the diverse trophoblast cell types in humans would be helpful to understand the pathogenesis of these pregnancy diseases.

During the past decade, transgenic mouse models that allow gene knock-out and gene targeting, have vastly improved our understanding of the genetic control of placental development in the mouse and have opened up new avenues of investigation in developmental biology. Despite considerable differences in placental development in mice and humans, some fundamental elements of placental development are similar in both species. Furthermore, certain key molecular regulators such as transcription factors involved in the expression of various placental genes have been described in both human and mouse placenta [9], [10], [11].