Growth Differentiation Factor 9 Is a Germ Cell Regulator of Sertoli Cell Function
Growth Differentiation Factor 9 Is a Germ Cell Regulator of Sertoli Cell Function
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DOI：
10.1210/en.2008-1048
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发表时间：
2009-05-01
期刊：
影响因子：
4.8
通讯作者：
Stanton, Peter G.
中科院分区：
文献类型：
--
作者：
Nicholls, Peter K.;Harrison, Craig A.;Stanton, Peter G.
卵母细胞分泌的生长分化因子（GDF）9和骨形态发生蛋白（BMP）15是雌性生殖的关键调节因子。它们共同促进颗粒细胞增殖并刺激排卵前卵泡的成熟。尽管GDF9和BMP 15在女性生育力中的重要性，但它们在精子发生过程中的表达模式和功能尚未研究。在这项研究中，我们表明，这两个因素的表达和阶段特异性定位仅限于大鼠生精上皮的生殖细胞，GDF9主要定位于圆形精子细胞和BMP 15在生殖母细胞和粗线期精母细胞。为了鉴定GDF9作用的潜在细胞靶标，分离生精小管细胞并筛选信号传导受体[激活素样激酶（ALK）5、ALK 6和BMP受体，II型]的表达。单个受体类型在整个生精上皮中表达，但ALK 5和BMP受体II型的共表达仅限于支持细胞和圆形精子细胞。基于卵巢和睾丸中相关TGF β配体的生殖作用，评估了GDF 9在大鼠支持细胞培养物中调节紧密连接功能和Escherichin B产生的能力。当重组小鼠GDF9被添加到未成熟的支持细胞培养物中时，它抑制了连接蛋白claudin-11、occludin和闭合小带-1的膜定位，从而破坏了紧密连接的完整性。同时，GDF9上调了BMP1蛋白亚基的表达，并显著刺激了二聚体BMP1蛋白B的产生。总之，这些结果表明，GDF9和BMP 15是大鼠睾丸中的生殖细胞特异性因子，并且GDF9可以调节关键的支持细胞功能。（内分泌学150：2481 - 2490，2009）
Oocyte-secreted growth differentiation factor (GDF) 9 and bone morphogenetic protein (BMP) 15 are critical regulatory factors in female reproduction. Together, they promote granulosa cell proliferation and stimulate the maturation of preovulatory follicles. Despite their importance in female fertility, GDF9 and BMP15 expression patterns and function during spermatogenesis have not been investigated. In this study we show that the expression and stage-specific localization of both factors are limited to the germ cells of the rat seminiferous epithelium, with GDF9 being principally localized in round spermatids and BMP15 in gonocytes and pachytene spermatocytes. To identify potential cellular targets for GDF9 actions, cells of the seminiferous tubule were isolated and screened for the expression of signaling receptors [activin-like kinase (ALK) 5, ALK6, and BMP receptor, type II)]. Individual receptor types were expressed throughout the seminiferous epithelium, but coexpression of ALK5 and BMP receptor, type II was limited to Sertoli cells and round spermatids. Based on the reproductive actions of related TGF beta ligands in the ovary and testis, GDF9 was assessed for its ability to regulate tight junction function and inhibin B production in rat Sertoli cell cultures. When recombinant mouse GDF9 was added to immature Sertoli cell cultures, it inhibited membrane localization of the junctional proteins claudin-11, occludin, and zonula occludens-1, thereby disrupting tight junction integrity. Concomitantly, GDF9 up-regulated inhibin subunit expression and significantly stimulated dimeric inhibin B protein production. Together, these results demonstrate that GDF9 and BMP15 are germ cell-specific factors in the rat testis, and that GDF9 can modulate key Sertoli cell functions. (Endocrinology 150: 2481-2490, 2009)