男性荷爾蒙受體在睪丸內個別細胞以及卵巢顆粒細胞中扮演 的角色

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Title:	男性荷爾蒙受體在睪丸內個別細胞以及卵巢顆粒細胞中扮演的角色 Androgen receptor (AR) physiological roles in individual testis cells and ovarian granulosa cells
Authors:	王瑞生 Wang, Ruey-Sheng
Keywords:	男性賀爾蒙受體;Sertoli細胞;Leydig細胞;生殖細胞;顆粒細胞;粒線體;androgen receptor;Sertoli cell;Leydig cell;germ cell;mitochondria
Date:	2014-07-04
Issue Date:	2018-10-15 11:42:59 (UTC+8)
Abstract:	Androgens/androgen receptor (AR) signaling is involved primarily in the development of male-specific phenotypes during embryogenesis, spermatogenesis, sexual behavior, and fertility during adult life. This signaling has also been shown to play an important role in female ovarian folliculogenesis. The recent generation and characterization of total and cell-specific AR knockout mice from different laboratories demonstrated the necessity of AR signaling for male phenotype development, normal spermatogenesis and ovarian folliculogenesis. To examine the role of AR in testicular Sertoli cells, we used a Sertoli cell-specific AR knockout (S-AR-/y) mouse to evaluate the chronological changes of seminiferous tubules and the molecular mechanisms of Sertoli cell androgen/AR signals on spermatogenesis. We found that testes morphology began changing as early as postnatal day (PD) 10.5 in male wild-type (AR+/y), but not in S-AR-/y mice. After puberty (PD 50), the Sertoli cell nuclei of AR+/y testes migrated to the basal area of the seminiferous epithelium; however, in S-AR-/y testes, Sertoli cell nuclei were disarranged and dislocated. Using quantitative RT-PCR analyses, the expression of Sertoli cell gene profiles were compared in PD 10.5 testes. In S-AR-/y testes, the expression levels of 1) vimentin were significantly increased and laminin α5 was significantly decreased in PD 10.5, which contributed to functional defects in cytoskeleton and production of the iii basement membrane component of Sertoli cell leading to cell morphology deterioration and thus affecting the integrity of seminiferous epithelium; 2) claudin-11, occludin, and gelsolin were significantly decreased in PD 10.5, which contributed to defects in intact junctional complex formation of Sertoli cell leading to impairment of the integrity of the blood-testis barrier (BTB); 3) calcium channel, voltage-dependent, P/Q-type, α1A subunit; tissue-type plasminogen activator; transferrin; and epidermal fatty-acid binding protein were significantly decreased in PD 10.5, which contributed to functional defects in production and/or secretion of specific proteases, transport proteins, and paracrine factors of Sertoli cell, leading to impairment of its germ cells’ nursery functions. The impact of lacking AR in Sertoli cells mainly affects Sertoli cell functions to support and nurture germ cells, leading to spermatogenesis arrest at the diplotene primary spermatocyte stage prior to the accomplishment of first meiotic division. To examine the role of AR in testicular germ cells, we used a germ cell-specific AR knockout (G-AR-/y) mouse to evaluate direct AR functions in male germ cells. We found that G-AR-/y exhibited normal fertility function. Histology analysis of G-AR-/y mice testes indicated that each stage of spermatogenesis is normal and the expression of AR in Sertoli, Leydig, and peritubular cells is unaffected. Sperm count and motility in epididymis from G-AR-/y mice are similar to that of the AR+/y mice. The fertility tests showed there was no difference when the AR+/y and G-AR-/y male mice were mated iv with wild type female mice (AR+/+). These data provide in vivo evidence showing male mice without AR in germ cells can still have normal spermatogenesis and fertility, suggesting the essential roles of AR during spermatogenesis might come from indirect cell-cell communication in a paracrine fashion. We then compared the consequences of AR loss in the spermatogenesis and fertility of G-AR-/y mice with two other testicular cell-specific AR-/y mice and total AR-/y (T-AR-/y) male mice. The results show clear in vivo evidence that androgen/AR signaling in Sertoli cells plays a direct important role in spermatogenesis and in Leydig cells plays an autocrine regulatory role to modulate Leydig cell steroidogenic function. T-AR-/y male mice have the most severe defects among these mice. These contrasting data with G-AR-/y mice suggest AR might have different roles in the various cells within testis to contribute to normal spermatogenesis and male fertility in mice. To examine the role of AR in ovarian granulosa cells, we used female AR knockout (AR-/-) mouse to evaluate the molecular mechanisms of granulosa cell androgen/AR signals on folliculogenesis and oocyte development. Earlier studies showed that mice lacking the androgen receptor (AR-/-) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. We found that v oocyte in vitro maturation rate was significantly poorer (60%) with loosened junction with granulosa cells in AR-/- female mice, whereas 95 % of AR+/+ oocytes had reached to metaphase II. Interestingly, we found these mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells.
Description:	博士委員-魏耀揮委員-謝榮鴻委員-王鵬惠指導教授-曾啟瑞委員-高淑慧
Data Type:	thesis
Appears in Collections:	[Graduate Institute of Clinical Medicine] Dissertation/Thesis

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