ACTIVIN REGULATION OF OVARIAN FOLLICLE DEVELOPMENT

卵泡的发育是一个复杂的过程，涉及卵泡的多种细胞类型之间的相互作用，需要局部产生和性腺外因子的作用。了解卵泡发育的控制对于控制生育和治疗不孕症具有重要的医学意义。我们已经建立了两种新的转基因小鼠模型，以研究TGF β家族蛋白激活素在卵泡正常和异常发育和排卵中的作用。我们的初步研究揭示了一个显着的频谱常见的卵巢病理小鼠表达的α亚基的激活素拮抗剂的Smadbin（MT-α）或显性负Smad 2转基因（Smad 2-DN）的转基因。在每种情况下，雌性小鼠生育能力低下，卵巢中发现异常的多卵细胞卵泡和大囊肿。连接这些观察结果的共同因素是激活素产生或作用的特定缺陷。在α亚基中， 在小鼠中，过量的α亚基与内源性激活素β亚基形成β-受体结合素异二聚体，从而局部降低激活素水平。在Smad 2-DN小鼠中，激活素信号通路的关键元件Smad 2被抑制。因此，该提议的中心假设是激活素在卵泡的正常发育中起关键作用。拟议的研究将通过调查三个相关的具体目标来检验这一假设。目的1将研究多卵卵泡的发育，并探索激活素在细胞间相互作用中的作用，从而建立一个合适的卵泡边界。目的2将确定是否新生儿雌激素暴露，一个已知的多卵细胞卵泡诱导剂，调节激活素或激活素信号蛋白，从而建立一个机制的联系，在这两个模型中的多卵细胞卵泡的形成。目的3研究卵巢囊肿在转基因小鼠模型中的形成，并建立其起源、与排卵过程和卵巢表面上皮的关系以及激活素的调控。总之， 该应用将提供对正常卵泡发育的新认识，建立正常发育被破坏导致异常卵巢病变（如多卵细胞卵泡和囊肿）的机制，并提供对这些重要生殖过程中激活素调节功能的新认识。

Development of the ovarian follicle is a complex process that involves interplay between the multiple cell types of the follicle and requires the actions of both locally produced and extragonadal factors. Understanding the control of follicle development has important medical implications for the control of fertility and the treatment of infertility. We have generated two novel transgenic mouse models to investigate the role of the TGFbeta family protein activin in normal and aberrant development and ovulation of the ovarian follicle. Our preliminary studies reveal a remarkable spectrum of common ovarian pathologies in mice that express transgenes for either the alpha subunit of the activin antagonist inhibin (MT-alpha) or a dominant-negative Smad2 transgene (Smad2-DN). In each case, the female mice are subfertile and both abnormal multi-oocytic follicles and large cysts are found in the ovary. The common element linking these observations is a specific deficiency in activin production or action. In the inhibin alpha subunit mice, the excess alpha subunit forms inhibin heterodimers with endogenous activin beta subunits, thus locally reducing activin levels. In the Smad2-DN mice, Smad2, a key element of the activin signaling pathway, is inhibited. Thus, the central hypothesis of this proposal is that activin plays a critical role in normal development of the ovarian follicle. The studies proposed will test this hypothesis by investigating three related specific aims. Aim 1 will examine the development ofmulti-oocytic follicles and explore roles for activin in cell-cell interactions leading to the establishment of an appropriate follicle boundary. Aim 2 will determine whether neonatal estrogen exposure, a known inducer of multi-oocytic follicles, acts to regulate activin or activin signaling proteins, thus establishing a mechanistic linkage for the formation of multi-oocytic follicles in these two models. Aim 3 will investigate the formation of ovarian cysts in these transgenic mouse models and establish their origin, association with the ovulatory process and the ovarian surface epithelium, and regulation by activin. In total, the studies described in this application will provide new insights into normal follicle development, establish the mechanisms by which normal development is disrupted leading to aberrant ovarian pathologies such as multi-oocytic follicles and cysts, and offer new insights into the functions of activin regulation in each of these important reproductive processes.