Clusterin (11. Uterus)

In the mouse, clusterin mRNA was expressed in uterine luminal and glandular epithelial cells coincident with the presence of clusterin protein. The clusterin gene was differentially expressed in the glandular and uterine luminal epithelial cells during the estrous cycle and following hormone depletion. Expression of clusterin was not induced in ovariectomized mice by estrogen, progesterone, or dexamethasone treatment alone. Progesterone administration after an initial estrogen pretreatment, however, resulted in dramatic induction of clusterin as the progesterone level declined. In contrast, clusterin was not induced when a long-lived progesterone analog, medroxyproges­terone, was substituted for progesterone. In the human menstrual cycle, clusterin was present in glandular lumens only during the late secretory phase. Declining progesterone levels, causing substantial tissue reorganization, are characteristic of the times of marked clusterin induction in uterine epithelial cells. These expression patterns are consistent with clusterin functioning as an extracellular cytoprotectant by mediating clearance of and/or neutralizing cytolytic tissue debris ^Ref .

Uterine clusterin gene activity was not detected immediately following fertilization, but glandular epithelial expression of clusterin mRNA appeared just before the time of blastocyst implantation and persisted postimplantation. During implantation, uterine luminal epithelial cells also expressed clusterin, but expression was excluded from luminal cells adjacent to the sites of attached blastocysts. Clusterin protein accumulated in the glandular and uterine lumens in proximity to the epithelial cells that expressed clusterin mRNA. It was suggested that clusterin expression is a marker of uterine receptivity to blastocyst implantation. Subsequent expression of clusterin message in uterine stromal cell types and in circular muscle myocytes coincided with the onset of decidualization. During this period the myocytes of the longitudinal muscle layer showed no evidence of clusterin mRNA. Clusterin protein was localized to nondecidualized tissue but was not evident in decidualized cells. In contrast, the protein was dispersed throughout both the circular and longitudinal myometrium. In the uteri of hormone-treated females stimulated with oil, clusterin was also expressed during decidualization in stromal cells and in circular myocytes, indicating that signals specifically transmitted from the embryo itself are not responsible for clusterin mRNA accumulation ^Ref .

Analysis of the expression of clusterin by quantitative reverse transcription-polymerase chain reaction detected an increase in the steady-state level of its transcripts in blastocysts from diabetic rats. In situ hybridization revealed that about half the cells identified as expressing clusterin mRNA exhibited signs of nuclear fragmentation. In vitro experiments demonstrated that high D-glucose increased nuclear fragmentation, tunel labeling and clusterin transcription. Tumor necrosis factor-alpha (TNF-alpha),a cytokine whose synthesis is up-regulated in the diabetic uterus, did not induce nuclear fragmentation nor clusterin expression but increased the incidence of TUNEL-positive nuclei. The data suggest that excessive cell death in the blastocyst, most probably resulting from the overstimulation of a basal suicidal program by such inducers as glucose and TNF-alpha, may be a contributing factor of the early embryopathy associated with maternal diabetes ^Ref .