Trophoblast cell lineages build the functional units of the organ, the placenta and are important for the anchorage of the embryo to the mother, for establishing a vascular connection for nutrient and gas transport to the embryo, and expression of hormones that are required for the successful progression of pregnancy. Defective development of the trophoblast cell lineages leads to either failure of embryo implantation or pregnancy associated disorders like preeclampsia. Thus it is important to understand molecular pathways that regulate development of the trophoblast cell lineages. The origination of trophoblast cell lineages starts with the establishment of the trophectoderm (TE), one of the first two cell lineages that are specified during preimplantation mammalian development. Gene knockout studies in mice showed that TEAD4, a member of TEA-domain containing transcription factors, is the master orchestrator of the TE-specific transcriptional program. TEAD4-null embryos do not mature to the blastocyst stage and lack expression of master regulators of trophoblast development, like CDX2, and GATA3. Interestingly, although TEAD4 specifically regulates TE/trophoblast-specific gene expression during early mouse development, direct targets of TEAD4 have not been identified in the TE or in trophoblast progenitors of the developing placenta. Furthermore, functional importance of TEAD4 during trophoblast lineage development after embryo implantation has not been tested. Thus, the molecular mechanisms by which TEAD4 regulates trophoblast lineage development are poorly understood. The goal of this proposal is to define molecular mechanisms by which TEAD4 selectively orchestrate a trophoblast stem cell-specific transcriptional program.
Two specific aims are proposed;
in aim 1, we will define global TEAD4-dependent transcriptional network in trophoblast cells. Using both mouse and rat as model systems, we will test the hypothesis that TEAD4 regulates a core TSC-specific transcriptional network within the TE of a preimplantation embryo. We will use chromatin immunoprecipitation along with genome wide sequencing (ChIP-Seq) to identify TEAD4 target genes in trophoblast cells and to define a global TEAD4-dependent, trophoblast-specific transcriptional network.
In aim 2, we will determine importance of TEAD4 in postimplantation trophoblast lineage development. We will test the hypothesis that similar to preimplantation TE-lineage development, TEAD4 function is also important to maintain expression of TSC-specific genes within the trophoblast progenitors of the developing placenta and impairment of TEAD4 function after embryo implantation will negatively affect development of trophoblast lineages.
Defect in the trophectderm and trophoblast lineage development is one of the major causes of early pregnancy loss, which is a major public health concern. In addition, placental development due to impaired trophoblast cell development and functions lead to pregnancies that are at risk for miscarriage and intrauterine growth retardation, and are associated with preeclampsia, a leading cause of maternal death and premature birth. Therefore, understanding the molecular mechanisms of development and function of trophoblast cell lineages is critical to gaining insights into important features of pregnancy loss and pregnancy associated disorders.
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