Apoptosis-regulating factors in developing and adult ovaries
1University of Oulu, Faculty of Medicine, Institute of Clinical Medicine, Department of Obstetrics and Gynecology
2Oulu University Hospital, Clinical Research Center
|Online Access:||PDF Full Text (PDF, 2.5 MB)|
|Persistent link:|| http://urn.fi/urn:isbn:9789514263477
Oulu : University of Oulu,
|Publish Date:|| 2010-11-16
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic dissertation to be presented with the assent of the Faculty of Medicine of the University of Oulu for public defence in Auditorium 4 of Oulu University Hospital, on 26 November 2010, at 12 noon
Doctor Tommi Vaskivuo
Professor Juha Tapanainen
Professor Sari Mäkelä
Professor Olli Ritvos
Apoptosis plays a crucial part in human ovarian function from fetal development to the end of reproductive potential. Failures in the regulation of ovarian apoptosis are associated with many pathological conditions such as premature ovarian insufficiency, infertility and cancer. The purpose of the present study was to analyze the factors regulating cell survival in human fetal and adult ovaries.
The fetus is exposed to maternal- and placental-derived estrogens and insufficient estrogen action has destructive effects on rodent ovarian development. We detected estrogen receptors and estrogen-converting enzymes in human fetal ovaries after primordial follicle formation, indicating that estrogens participate in human fetal ovarian development, especially after folliculogenesis.
The WNT4 gene is crucial for female sexual differentiation, follicle formation and oocyte survival. We detected WNT4 in follicular cells of fetal and adult human ovaries. In addition, Wnt4- knockout mice demonstrated a dramatic loss of oocytes before birth. However, no changes were detected in protein expression patterns of common apoptosis-related proteins. The results support the possible role of WNT4 in human ovarian function and strengthen previous knowledge on the antiapoptotic role of Wnt4.
Apoptosis signaling is mediated by extracellular- and mitochondria-associated- pathways, ending in caspase cascade activation and fragmentation of cellular structures. In the present study we analyzed the expression of several apoptosis-related factors and detected TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries. In addition, TRAIL was found to be a potent and rapid inducer of human granulosa tumor cell (KGN) apoptosis. Lentiviral downregulation of Bok or Bcl-XL protein expression in KGN cells also resulted in significant changes in cell vulnerability to apoptosis. The results show for the first time the spatiotemporal expression patterns of TRAIL, TNF, Bcl-XL, Bok and caspase-3 in human ovaries and suggest an important functional role of TRAIL, Bok and Bcl-XL in regulation of human ovarian apoptosis.
The present study offers novel information on the expression and function of cell survival factors in human ovaries. These new findings open possibilities for future clinical research in attempts to understand and treat ovarian diseases caused by imbalanced regulatory pathways of apoptosis.
Acta Universitatis Ouluensis. D, Medica
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