Abstract
BackgroundIn higher primates, although LH/CG play a critical role in the control of corpus luteum (CL) function, the direct effects of progesterone (P4) in the maintenance of CL structure and function are unclear. Several experiments were conducted in the bonnet monkey to examine direct effects of P4 on gene expression changes in the CL, during induced luteolysis and the late luteal phase of natural cycles.MethodsTo identify differentially expressed genes encoding PR, PR binding factors, cofactors and PR downstream signaling target genes, the genome-wide analysis data generated in CL of monkeys after LH/P4 depletion and LH replacement were mined and validated by real-time RT-PCR analysis. Initially, expression of these P4 related genes were determined in CL during different stages of luteal phase. The recently reported model system of induced luteolysis, yet capable of responsive to tropic support, afforded an ideal situation to examine direct effects of P4 on structure and function of CL. For this purpose, P4 was infused via ALZET pumps into monkeys 24 h after LH/P4 depletion to maintain mid luteal phase circulating P4 concentration (P4 replacement). In another experiment, exogenous P4 was supplemented during late luteal phase to mimic early pregnancy.ResultsBased on the published microarray data, 45 genes were identified to be commonly regulated by LH and P4. From these 19 genes belonging to PR signaling were selected to determine their expression in LH/P4 depletion and P4 replacement experiments. These 19 genes when analyzed revealed 8 genes to be directly responsive to P4, whereas the other genes to be regulated by both LH and P4. Progesterone supplementation for 24 h during the late luteal phase also showed changes in expression of 17 out of 19 genes examined.ConclusionThese results taken together suggest that P4 regulates, directly or indirectly, expression of a number of genes involved in the CL structure and function.
Highlights
In higher primates, LH/chorionic gonadotropin (CG) play a critical role in the control of corpus luteum (CL) function, the direct effects of progesterone (P4) in the maintenance of CL structure and function are unclear
Experiment 3: Effects of P4 replacement on expression of progesterone receptor (PR), coactivators, corepressors and P4 target genes during induced luteolysis We have recently reported that replacement of LH post LH/P4 depletion leads to brisk and sustained increase in P4 concentration suggesting rescue of CL function following reestablishment of LH levels [16]
The published microarray data was mined for P4¬ responsive genes, and 45 differentially expressed genes were identified based on criteria of >1.5 fold change in both LH/P4 depletion and LH replacement experiments
Summary
LH/CG play a critical role in the control of corpus luteum (CL) function, the direct effects of progesterone (P4) in the maintenance of CL structure and function are unclear. Several experiments were conducted in the bonnet monkey to examine direct effects of P4 on gene expression changes in the CL, during induced luteolysis and the late luteal phase of natural cycles. It has been reported that decrease in P4 levels during late luteal phase of the non fertile cycle is associated with changes in expression of ECM regulators [20]. It remains to be determined whether P4 regulates expression of tissue proteinases, especially following conception. Experiments were carried out to determine expression of genes in CL tissue that encode different elements of PR complex and few downstream targets of PR activation throughout the luteal phase, after LH/P4 depletion, after P4 replacement and after P4 supplementation during the late luteal phase
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