טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSavulescu Dana
SubjectThe Role of Prohibitin in GnRH-Induced Cell Death in
Gonadotropes
DepartmentDepartment of Biology
Supervisor Professor Philippa Melamed
Full Thesis textFull thesis text - English Version


Abstract

The gonadotropes are the population of cells in the pituitary that plays a pivotal role in the mammalian reproductive system. When exposed to Gonadotropin-releasing hormone (GnRH), these cells undergo several intracellular modifications leading to production and secretion of the Follicle-stimulating hormone (FSH) and the Luteinizing hormone (LH). GnRH is also involved in the gonadotrope development, and we have already reported that it induces cell proliferation in immature, partially differentiated gonadotropes, while leading to apoptosis in mature, fully differentiated gonadotropes. Several MAPK cascades are activated by GnRH in the gonadotropes, but the downstream mechanisms responsible for mediating the GnRH-induced cell proliferation and death have not been elucidated yet. We have previously reported that the protein levels of prohibitin, a protein involved in cell proliferation regulation, are higher in the nuclei of mature gonadotropes compared to those of immature gonadotropes. We hypothesize that prohibitin plays a crucial role in the GnRH-induced apoptosis in mature gonadotropes.

In the current study, we show that the GnRH-induced apoptosis in mature gonadotropes is at least partially mediated by JNK, and that prohibitin plays a crucial role in this effect. We also show that GnRH increases the transcript levels of prohibitin and induces its nuclear export in mature gonadotropes. Additionally, our results show that prohibitin is involved in mitochondrial import of the pro-apoptotic protein Bax in mature gonadotropes, and that GnRH induces an increase in Bax levels in these cells via the JNK pathway. GnRH also induces a JNK-mediated increase in the pro-apoptotic protein Hrk, which is also involved in the apoptotic response of mature gonadotropes to GnRH. Additionally we provide evidence for the down regulation of prohibitin levels by miR27 in immature gonadotropes. Our results show that miR27 is expressed in higher levels in immature gonadotropes compared to mature gonadotropes, and suggest that miR27 inhibits the GnRH-induced apoptosis via targeting prohibitin in immature cells. We also show here that mice with targeted knock down of prohibitin in gonadotropes display various reproductive abnormalities including a larger gonadotrope population, increased LH levels, reduced fertility and altered gonad size and morphology. Collectively, our findings suggest that prohibitin plays a crucial role in GnRH-induced cell death in mature gonadotropes and that this role is important for the development and function of the reproductive axis.