Proper development of the placenta is paramount for fetal growth and viability. Maldevelopment of the placenta causes several complications of pregnancy, increasing the risk of morbidity and mortality for both mothers and newborn babies. A better understanding of the molecular networks that govern normal placental development will significantly improve our understanding of the pathogenesis of these pregnancy complications. Several specialized subtypes of trophoblast cells comprise the epithelial component of the placenta. One subtype - syncytiotrophoblast - is a unique, multinucleated lineage that forms the primary barrier between maternal and fetal circulations. Syncytiotrophoblast is continuously formed throughout pregnancy by cytoplasmic fusion of mononuclear cytotrophoblast cells. Fusion is a complex process catalyzed by human endogenous retrovirus-derived syncytin genes. Our primary objective is to define transcriptional networks that regulate the expression of syncytin genes and syncytiotrophoblast formation. Through microarray analysis, we are the first to identify that the conserved transcription factor OVOL1 is highly induced in a model of human syncytiotrophoblast formation. OVOL1 has been implicated in the regulation of epithelial differentiation in many species;however, its role in human trophoblast differentiation is not known. In preliminary analyses, we observed that depletion of OVOL1 has intriguing effects on the differentiation capacity of trophoblast cells. To more thoroughly assess the role of OVOL1 in syncytiotrophoblast formation, we propose compelling experiments outlined in two Aims.
Aim 1 will determine what happens to the differentiation potential of human trophoblast cells when OVOL1 expression is manipulated.
Aim 2 will determine how OVOL1 fits into a gene regulatory network controlling retrovirus-derived gene expression and consequently, syncytialization. We expect information accrued from experiments in Aims 1 and 2 will provide pertinent information on trophoblast syncytialization, and will shed new light on the molecular regulation of placental development. We also expect that the information garnered from these studies will provide an important foundation in our quest to understand the molecular signals governing placental development in both normal and pathological pregnancies.
Proper development of the placenta is essential for fetal development and pregnancy success. Trophoblast cells comprise the epithelial component of the placenta and perform many of its functions. Understanding the molecular mechanisms that regulate trophoblast differentiation is critical for gaining insights into placenta-associated disorders that can negatively impact maternal and fetal health.
|Renaud, Stephen J; Chakraborty, Damayanti; Mason, Clifford W et al. (2015) OVO-like 1 regulates progenitor cell fate in human trophoblast development. Proc Natl Acad Sci U S A 112:E6175-84|