During human trophoblast differentiation, mononuclear cytotrophoblast cells of the placental villous differentiate to form a multinucleated syncytium that synthesizes and secretes many growth factors and steroid hormones that are important maternal and fetal regulators. Our laboratory is studying the differentiation of primary cultures of villous cytotrophoblast cells, using the induction of human placental lactogen (hPL), human chorionic gonadotropin (hCG) and several other genes as fundamental markers of syncytiotrophoblast cell development. We have observed that there are two distinct phases of cytotrophoblast differentiation: morphological differentiation, during which the mononuclear cytotrophoblast cells fuse to form a syncytium, and biochemical differentiation, during which the syncytiotrophoblast cells develop differentiated functions such as hormone production. The overall hypothesis of this proposal is that morphological differentiation depends on transcription factors that induce syncytin, a protein known to be critical for syncytium formation in BeWo choriocarcinoma cells, and that biochemical differentiation depends on the activity of the transcription factor AP-2a, which we have shown to be critical for the induction of several syncytiotrophoblast genes. We postulate that the induction of AP-2a leads to transcriptional induction and repression of groups of downstream transcription factors and other target genes essential for syncytiotrophoblast function; and disruption of AP-2a action or syncytin expression may lead to placental disorders such as choriocarcinoma, hydatidiform mole and pre-eclampsia.
The specific aims are to test the hypotheses that 1) the syncytin and AP-2cz genes are coordinately regulated during cytotrophoblast differentiation by cAMP, steroid hormones, and inflammatory cytokines; 2) the induction of syncytin expression is critical for syncytium formation during villous cytotrophoblast cell differentiation, and 3) AP- 2-dependent transcription factors and growth factors direct a genetic program that is critical for hormone production and other biochemical processes essential for human cytotrophoblast differentiation and function. Methodologies will include transfection studies, gel shift assays, and DNA microarray analyses. New knowledge about the genetic program that directs normal trophoblast differentiation may lead to the development of novel approaches for the treatment of placental tumors, pre-eclampsia, and other pathological conditions associated with abnormal placental development

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Med Ctr (Cincinnati)
United States
Zip Code
Brown, Allen W; Leibson, Cynthia L; Mandrekar, Jay et al. (2014) Long-term survival after traumatic brain injury: a population-based analysis controlled for nonhead trauma. J Head Trauma Rehabil 29:E1-8
Leibson, Cynthia L; Brown, Allen W; Hall Long, Kirsten et al. (2012) Medical care costs associated with traumatic brain injury over the full spectrum of disease: a controlled population-based study. J Neurotrauma 29:2038-49
Leibson, Cynthia L; Brown, Allen W; Ransom, Jeanine E et al. (2011) Incidence of traumatic brain injury across the full disease spectrum: a population-based medical record review study. Epidemiology 22:836-44
Hubert, Michael A; Sherritt, Susan L; Bachurski, Cindy J et al. (2010) Involvement of transcription factor NR2F2 in human trophoblast differentiation. PLoS One 5:e9417
Handwerger, Stuart (2010) New insights into the regulation of human cytotrophoblast cell differentiation. Mol Cell Endocrinol 323:94-104
Chabas, D; Ness, J; Belman, A et al. (2010) Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 74:399-405
Kessler, Cherie A; Bachurski, Cindy J; Schroeder, Jennifer et al. (2008) TEAD1 inhibits prolactin gene expression in cultured human uterine decidual cells. Mol Cell Endocrinol 295:32-8