| dc.description.abstract | Mammalian embryonic development depends on the indispensable contribution of a transient dynamic organ, the placenta, which supports the pregnancy during the entire gestational days. The placenta provides hormones to regulate fetal development, act as the nutrient exchange surface and as a protective barrier for the fetus during its most crucial initial days inside the mother’s uterus. Impaired development of such a crucial organ will imperatively lead to pregnancy associated disorders including preterm birth, intrauterine growth retardation (IUGR), preeclampsia and even the severe form of eclampsia. A lot of research studies are now focusing on the disruptive effects of placental disorders, most of which are molecular signaling anomalies leading to defective trophoblast lineage development. Also, many of the embryonic lethal mouse mutants have been found to be associated with placental insufficiency not reported before, which is the most vital underlying molecular cause for embryonic death. In humans, atleast 40% of all pregnancies undergo spontaneous miscarriages and the etiology for these cases and others like recurrent pregnancy losses (RPLs) remains unknown. For ethical reasons studying human tissues and subjects remain tightly regulated. Alternatively, rodents, which also exhibit hemochorial placentation similar to humans, have been used as a powerful model to study the molecular mechanisms important for placentation. In this study, we have identified one of the key conserved signaling mechanism which we believe is essential for the proper development of the placenta both in rodents as well as in humans. Earlier research have shown the importance of Protein Kinase C (PKC) isoform, Atypical PKC iota (PKCλ/ι) in embryonic stem (ES) cells and mitochondrial biogenesis in self-renewing versus differentiating ES cells, however the functional importance of PKCλ/ι in the trophoblast lineage development remained oblivious despite of embryonic lethal phenotype upon global deletion of the gene coding PKCλ/ι, Prkci in mouse. In this study, we have used the global knockout mouse model of Prkci gene and we show that PKCλ/ι is essential for the establishment of the maternal-fetal exchange surface made up of trophoblast cell subtype called the syncytiotrophoblasts (SynTs). Our analyses using mouse and human trophoblast stem (TS) cells indicate the essentiality of PKCλ/ι in establishing the differentiation program in trophoblast progenitors towards SynTs. Our whole genomic analyses, using PKCλ/ι depleted mouse and human TS cells, reveal that known regulators of SynT development such as GATA-binding factor 2 (GATA2) and Peroxisome proliferator-activated receptor gamma (PPARG), act downstream of PKCλ/ι signaling. GATA2 and PPARG in turn regulates GCM1/DLX3 signaling axis. Both GATA2 and PPARG undergoes significant downregulation in protein and mRNA expression thus impairing SynT establishment in PKCλ/ι depleted mouse and human TS cells. In the second part of this study, we have analyzed a conditional knockout mouse model of Prkci, where it is deleted using a Cre-mediated recombination, specifically, in the Syncytiotrophoblast II (SynT-II) cells of mouse placenta. Our results so far indicate that homozygous deletion of Prkci allele in the SynT-II cells causes developmental defects amounting to embryonic lethality in these mutants. Summarizing the whole study, we have identified novel, evolutionary conserved functional importance of Atypical Protein Kinase C isoform PKCλ/ι in inducing differentiation program within trophoblast progenitors towards the establishment of the maternal–fetal exchange surface from mouse to humans. | |
