Thyrostimulin, but not thyroid-stimulating hormone (TSH), acts as a paracrine regulator to activate the TSH receptor in mammalian ovary.
The thyroid-stimulating hormone receptor (TSHR), activated by either TSH or the newly discovered glycoprotein hormone thyrostimulin, plays a central role in the control of body metabolism. Interestingly, in addition to its thyroid expression, we discovered that the mRNA level of TSHR is periodically regulated in rat ovary by gonadotropins. Ovarian microdissection followed by real-time PCR analysis indicated that granulosa cells show the highest level of TSHR expression. Cultures of follicles and primary granulosa cells demonstrated that the level of TSHR is up-regulated and decreased 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 expressed mainly in oocytes. Evolving before the appearance of gonadotropins, thyrostimulin is considered the most ancestral glycoprotein hormone. Therefore, the presence of thyrostimulin in the ovary suggests that 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 show that 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 treatments with thyrostimulin significantly increase cAMP production and the c-fos gene response in the presence of gonadotropins. Thus, this study demonstrates that oocyte-derived thyrostimulin and granulosa cell-expressed TSHR compose a novel paracrine system in the ovary, where the activity is tightly controlled by gonadotropins.
Sun
Su-Chin
SC
From the Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112 and.
Hsu
Pei-Jen
PJ
From the Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112 and.
Wu
Fang-Ju
FJ
From the Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112 and.
Li
Sheng-Hsiang
SH
the Department of Medical Research, Mackay Memorial Hospital, Tamshui, Taipei Country 251, Taiwan.
Lu
Chung-Hao
CH
the Department of Medical Research, Mackay Memorial Hospital, Tamshui, Taipei Country 251, Taiwan.
Luo
Ching-Wei
CW
From the Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112 and. Electronic address: cwluo@ym.edu.tw.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006062:Gonadotropins / Q000494:pharmacology; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010053:Ovary / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019899:Paracrine Communication; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D006023:Glycoproteins; D006062:Gonadotropins; D016760:Proto-Oncogene Proteins c-fos; D011989:Receptors, Thyrotropin; C458339:thyrostimulin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004958:Estradiol; D013972:Thyrotropin; D000242:Cyclic AMP