Current topicHomeobox genes and down-stream transcription factor PPARγ in normal and pathological human placental development
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].
Section snippets
Transcriptional control of placental development
The differentiation of trophoblasts to either syncytiotrophoblast or “invasive trophoblast” represents the fundamental, alternative cell fate decision in the trophoblast lineage. During the formation of these distinct trophoblast cell types, different genetic programs are initiated including production of trophoblast cell-type specific hormones. To date, studies reveal that particular transcriptional regulators control specific placental hormone gene expression. Most placental hormones are
Homeobox genes
Homeobox genes (also known as homeotic genes) were originally discovered in the fruit fly Drosophila melanogaster, where they act as transcriptional regulators to control embryonic morphogenesis [17], [18], [19], [20]. These genes contain a highly conserved 180 base pair homeobox sequence, which encodes a 60 amino acid homeodomain. Structural analyses have shown that the homeodomain consists of an evolutionarily conserved helix-turn-helix motif that binds to the DNA. The specificity of this
Homeobox genes in murine placental development
Given the highly important role of homeobox genes in embryonic and adult development, it is not surprising that homeobox genes also play major roles in controlling extraembryonic development of the placenta. Homeobox genes regulate mouse placental cell functions and targeted gene mutations of homeobox genes in the mouse produce FGR-like effects. For example, homeobox gene mouse mutants, Esx1 and Dlx3, produce FGR-like effects in mice including restricted fetal growth and placental defects.
Homeobox genes in human placental development
Understanding the role of homeobox genes in human placental development and their functional role in pregnancy pathologies including fetal growth restriction and preeclampsia is highly important. A strategy for understanding the molecular mechanisms of placental function in normal and pathological human placentas requires (i) determining the spatio-temporal expression pattern of homeobox genes during placental development that have an “evolutionary history” of regulating cell fate decisions
Spatio-temporal expression patterns of homeobox genes in the placenta
Studies in the human placenta have focused mainly on identifying homeobox genes expressed in the normal placenta [67], [68], and those showing altered expression in trophoblastic cancers [69]. The homeobox genes we and others have identified to be of potential importance in the human placenta are DLX3, DLX4, GAX, ESX1L and HLX [15], [16], [55], [59], [60], [70]. These genes are also expressed in the embryo and play major roles in embryonic development [71], [72]. More specifically, we have
PPARγ, placental development and trophoblast differentiation (for review see [128,129])
In 1999, genetic studies performed in mice established that RXRs and PPARγ are essential for placental development and vasculature. Indeed, RXRα−/−/RXRβ−/− conceptuses fail to develop a normal chorioallantoic placenta with a functional labyrinthine zone, resulting in compromised maternal–fetal exchanges and therefore in early embryonic death at embryonic day E9.5 [130]. Likewise, PPARγ−/− conceptuses exhibited similar placental agenesis with defects in trophoblast differentiation and vascular
PPARγ target genes in human trophoblasts and involvement in gestational diseases
It was shown that like in other PPARγ target cells, PPARγ and its heterodimeric nuclear receptor partner RXRα regulate fatty acid uptake by trophoblast [144]. Analysis of PPARγ-target genes in the human trophoblast led to the discovery of known and new factors involved in the regulation of human trophoblast invasion [145], [146]. Among those, the human placental growth hormone (hPGH), the pregnancy-associated plasma protein A (PAPP-A) [147] and more recently the human chorionic gonadotropin
Conclusions and future directions
Our current understanding of how homeobox genes regulate trophoblast functions reveals that important aspects of transcriptional regulation are conserved between the extraembryonic placenta and embryonic morphogenetic and differentiation events. The strategy we have employed has resulted in the identification of homeobox genes, which are expressed in normal placental development and that show altered expression in FGR. Functional assays following target gene inactivation in cultured cells
Acknowledgments
We thank the consenting patients and the clinical and research midwives of Royal Women's Hospital, Melbourne, Australia and the Department of Obstetrics and Gynecology of Saint Vincent Hospital, Paris, France for providing placental tissues. We acknowledge the funding support for this work by Australian National Health and Medical Research Council (NHMRC grant #509140 to Dr. P. Murthi), INSERM and Université Paris Descartes, and “la Caisse d'Assurance Maladie des Professions Libérales de
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