Deciphering the luteal transcriptome: potential mechanisms mediating stage-specific luteolytic response of the corpus luteum to prostaglandin F_2α

Abstract

The objective of this study was to identify prostaglandin F(2α) (PG)-induced changes in the transcriptome of bovine corpora lutea (CL) that are specific to mature, PG-responsive (day 11) CL vs. developing (day 4) CL, which do not undergo luteolysis in response to PG administration. CL were collected at 0, 4, and 24 h after PG injection on days 4 and 11 of the estrous cycle (n = 5 per day and time point), and microarray analysis was performed with GeneChip Bovine Genome Arrays. Data normalization was performed with affy package and significance testing with maanova from Bioconductor. Significance (relative to 0 h time point) was declared at fold change >2.0 or <0.5 and false discovery rate of <5%. At 4 and 24 h after PG, 221 (day 4) and 661 (day 11) and 248 (day 4) and 1,421 (day 11) regulated genes, respectively, were identified. The accentuated gene expression response in day 11 CL was accompanied by specific enrichment of PG-regulated genes in distinctive gene ontology categories (immune related and other), particularly at 24 h after injection. Specificity in putative transcription factor binding sites was observed among PG-regulated genes on day 11 vs. day 4, including a potential association of ETS transcription factors with acute PG-induced gene expression specific to day 11 CL. Temporal and PG-induced regulation of abundance of mRNA for ETS transcription factor family members linked to the stage-specific response to PG was not observed. Increased abundance of protein and/or mRNA for six PG-regulated putative ETS-responsive genes was noted in day 11 but not day 4 CL. Results reveal insight into stage-specific gene expression in bovine CL in response to PG and potential transcriptional mediators of luteolysis.

Toll-like receptor 2 and 4 expression in the bovine corpus luteum during the different stages of the estrous cycle

“…Specifically, during luteolysis, immune cell infiltration to the CL increases (Penny, 2000) and they are considered to play a role in luteolysis. Although these immune cells are not responsive to PGF 2α in dCL, luteal cells respond to PGF 2α by increasing the expression of those genes that have regulatory functions on immune cells in mCL (Mondal et al, 2011). Therefore, the stimulation of TLR expression in luteal cells in mCL and rCL as observed in the present study may relate to an increased active immune status of the CL.…”

“…Since PKCε is a critical component of TLR4 signaling (McGettrick et al, 2006) and expression of both PKCε and TLR4 increased at the same stages of the CL, TLR4 is possibly a critical component for the PGF 2α response in the CL, implying a potential role of TLR4 in the acquisition of luteolytic capacity. Similarly, immune related genes increased only after PGF 2α induction in mCL compared to dCL (Mondal et al, 2011). Moreover, enhanced populations of specific types of immune cells and cell-to-cell communication between immune and the other types of CL cells in the mature stage clearly indicate immune regulation of the luteolytic pathway (Poole and Pate 2012;Penny 2000).…”

“…Bovine CL, during the developing stages, does not respond to luteolytic PGF 2α injection (Mondal et al, 2011). One of the reasons for this non-responsiveness was proposed in a recent study (Sen et al, 2006) in which expression levels of PKCε were found to increase 10-fold in mCL compared to dCL.…”

“…Therefore, the stimulation of TLR expression in luteal cells in mCL and rCL as observed in the present study may relate to an increased active immune status of the CL. As the immune cells and their signaling molecules have been linked to progesterone production and its regulation (Liptak et al, 2005;Mondal et al, 2011), the progesterone-producing luteal cells may undergo immune-cell like changes to cooperate in the mechanism of luteal maturation and regression.…”

Prostaglandin F2α induces expression of activating transcription factor 3 (ATF3) and activates MAPK signaling in the rat corpus luteum

“…Recent study showed that PGF 2␣ administration suppressed the expression of luteotropic factors and stimulated the expression of luteolytic factors that contributed to functional luteolysis (Berisha et al, 2010). Furthermore, there were multiple studies suggesting that PGF 2␣ could induce mRNA for many pathways and set the stage-specific gene expression that resulted in luteolysis (Atli et al, 2012;Bishop et al, 2012;Mondal et al, 2011). PGF binds and activates a Gqcoupled receptor on its target cells to activate phospholipase C, which results in increased free intracellular calcium (Currie et al, 1992;Davis et al, 1987;Rodway et al, 1992) and PKC activity (Davis et al, 1989).…”