Knight Philip G, Glister Claire
School of Animal and Microbial Sciences, University of Reading, Whiteknights, Reading RG6 6AJ, UK.
Anim Reprod Sci. 2003 Oct 15;78(3-4):165-83. doi: 10.1016/s0378-4320(03)00089-7.
Members of the transforming growth factor-beta (TGF-beta) superfamily have wide-ranging influences on many tissue and organ systems including the ovary. Two recently discovered TGF-beta superfamily members, growth/differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15; also designated as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play a key role in promoting follicle growth beyond the primary stage. Follicle growth to the small antral stage does not require gonadotrophins but appears to be driven by local autocrine/paracrine signals from both somatic cell types (granulosa and theca) and from the oocyte. TGF-beta superfamily members expressed by follicular cells and implicated in this phase of follicle development include TGF-beta, activin, GDF-9/9B and several BMPs. Acquisition of follicle-stimulating hormone (FSH) responsiveness is a pre-requisite for growth beyond the small antral stage and evidence indicates an autocrine role for granulosa-derived activin in promoting granulosa cell proliferation, FSH receptor expression and aromatase activity. Indeed, some of the effects of FSH on granulosa cells may be mediated by endogenous activin. At the same time, activin may act on theca cells to attenuate luteinizing hormone (LH)-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection appears to depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Activin may contribute to this selection process by sensitizing those follicles with the highest "activin tone" to FSH. Production of inhibin, like oestradiol, increases in selected dominant follicles, in an FSH- and insulin-like growth factor-dependent manner and may exert a paracrine action on theca cells to upregulate LH-induced secretion of androgen, an essential requirement for further oestradiol secretion by the pre-ovulatory follicle. Like activin, BMP-4 and -7 (mostly from theca), and BMP-6 (mostly from oocyte), can enhance oestradiol and inhibin secretion by bovine granulosa cells while suppressing progesterone secretion; this suggests a functional role in delaying follicle luteinization and/or atresia. Follistatin, on the other hand, may favor luteinization and/or atresia by bio-neutralizing intrafollicular activin and BMPs. Activin receptors are expressed by the oocyte and activin may have a further intrafollicular role in the terminal stages of follicle differentiation to promote oocyte maturation and developmental competence. In a reciprocal manner, oocyte-derived GDF-9/9B may act on the surrounding cumulus granulosa cells to attenuate oestradiol output and promote progesterone and hyaluronic acid production, mucification and cumulus expansion.
转化生长因子-β（TGF-β）超家族成员对包括卵巢在内的许多组织和器官系统都有广泛影响。最近发现的两个TGF-β超家族成员，即生长/分化因子-9（GDF-9）和骨形态发生蛋白-15（BMP-15；也称为GDF-9B），从很早阶段就以卵母细胞特异性方式表达，并在促进卵泡生长超越初级阶段中起关键作用。卵泡生长到小窦状卵泡阶段不需要促性腺激素，而是似乎由来自体细胞类型（颗粒细胞和卵泡膜细胞）以及卵母细胞的局部自分泌/旁分泌信号驱动。卵泡细胞表达并参与卵泡发育这一阶段的TGF-β超家族成员包括TGF-β、激活素、GDF-9/9B和几种骨形态发生蛋白。获得促卵泡激素（FSH）反应性是卵泡生长超越小窦状卵泡阶段的先决条件，证据表明颗粒细胞来源的激活素在促进颗粒细胞增殖、FSH受体表达和芳香化酶活性方面具有自分泌作用。事实上，FSH对颗粒细胞的一些作用可能由内源性激活素介导。同时，激活素可能作用于卵泡膜细胞，以减弱中小窦状卵泡中促黄体生成素（LH）依赖性雄激素的产生。优势卵泡的选择似乎取决于一群生长中的小窦状卵泡对FSH的不同敏感性。激活素可能通过使那些“激活素水平”最高的卵泡对FSH敏感来促进这一选择过程。抑制素的产生与雌二醇一样，在选定的优势卵泡中以FSH和胰岛素样生长因子依赖性方式增加，并可能对卵泡膜细胞发挥旁分泌作用，以上调LH诱导的雄激素分泌，这是排卵前卵泡进一步分泌雌二醇的必要条件。与激活素一样，BMP-4和-7（主要来自卵泡膜细胞）以及BMP-6（主要来自卵母细胞）可以增强牛颗粒细胞的雌二醇和抑制素分泌，同时抑制孕酮分泌；这表明其在延迟卵泡黄体化和/或闭锁方面具有功能作用。另一方面，卵泡抑素可能通过对卵泡内激活素和骨形态发生蛋白进行生物中和而有利于黄体化和/或闭锁。激活素受体由卵母细胞表达，激活素在卵泡分化的终末阶段可能在卵泡内具有进一步作用，以促进卵母细胞成熟和发育能力。以相反的方式，卵母细胞来源的GDF-9/9B可能作用于周围的卵丘颗粒细胞，以减少雌二醇输出并促进孕酮和透明质酸的产生、黏液化和卵丘扩展。
