|
Comment |
Thyrostimulin, but not thyroid-stimulating hormone, acts as a paracrine regulator to activate thyroid-stimulating hormone receptor in the mammalian ovary. Sun SC et al. Thyroid-stimulating hormone receptor (TSHR), activated by either TSH or a newly discovered glycoprotein hormone thyrostimulin, plays a central role in the control of body metabolism. Interestingly, in addition to its thyroid expression, we discovered the mRNA level of THSR is periodically regulated in the rat ovary by gonadotropins. Ovarian microdissection followed by real-time PCR analysis indicated granulosa cells show the highest level of TSHR expression. Cultures of follicles and primary granulosa cells demonstrated the level of TSHR is up-regulated and dampened by the gonadotropin-driven cAMP cascade and estradiol production, respectively. Furthermore, in contrast to the negligible expression of TSH in the ovary, we also found by real-time PCR and immunohistochemical analysis that thyrostimulin is mainly expressed in oocytes. Thyrostimulin, evolving before the appearance of gonadotropins, is considered the most ancestral glycoprotein hormone. Therefore, the presence of thyrostimulin in the ovary suggests it may have a primitive function in reproduction when it activates ovarian TSHR. Next, we generated recombinant thyrostimulin protein and characterized its non-covalent heterodimeric nature. Using purified recombinant thyrostimulin, we showed the human ovarian cell line NIH:OVCAR-3 also expresses endogenous and functional TSHR. Using cultured rat granulosa cells isolated from different ovarian stages, we found that treatment with thyrostimulin increased the cAMP production and c-fos gene response significantly in the presence of gonadotropins. Thus, this study demonstrates that oocyte-derived thyrostimulin and granulosa cell-expressed TSHR comprise a novel paracrine system in the ovary, where the activity is tightly controlled by gonadotropins.
|