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Regulation of Ovarian Granulosa Cell Proliferation and Differentiation by the Notch Signaling Pathway

机译：Notch信号通路对卵巢颗粒细胞增殖和分化的调控

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摘要

The follicle is the functional unit of the mammalian ovary and serves as a tightly controlled microenvironment where granulosa cells nurture the growth and maturation of the oocyte. Early events in follicular development are autonomous of the hypothalamic-pituitary-gonadal axis and are instead controlled by local factors that are used in bidirectional communication between oocytes and somatic cells. Following puberty, gonadotropins will eventually become the principle regulators of follicular growth, maturation, and ovulation. It is becoming increasingly appreciated that gonadotropin actions are achieved through interactions with local intraovarian signals. This thesis explores the functions of one such local intraovarian regulator, the Notch signaling pathway, at multiple distinct stages of ovarian follicular development.;The Notch pathway is a highly conserved cell-contact dependent juxtacrine signaling system and is an important regulator of primordial follicle formation in the mouse ovary. Using a reporter mouse line for identification of Notch active cells, continued Notch activity was observed in granulosa cells of follicles belonging to both the gondatropin independent and dependent stages of development. Based on this observation, I hypothesized that the Notch signaling pathway regulates distinct follicular functions at multiple stages of development to promote the overall health of the follicle. Active Notch signaling in granulosa cells was associated with greater proliferative capacity at the prepubertal age of postnatal day (PND) 21. The mitogenic function of Notch signaling was further confirmed using conditional knockout lines of the ligand Jag1 from germ cells (J1KO) or the receptor Notch2 from granulosa cells (N2KO) where suppressed proliferation in the ovary was observed at PND19. Significantly extending the understanding of Notch signaling during the gonadotropin-independent stage of follicular growth, a potential mechanism for Notch signaling propagation across multiple layers of granulosa cells in growing follicles was described. Activation of Notch signaling in granulosa cells led to increased expression of Jag1 ligand, which can transactivate Notch receptors on neighboring granulosa cells, consistent with a lateral induction mechanism.;Notch activity and expression of Notch ligands and receptors in the ovary were shown to be positively regulated following LH-receptor activation by exogenous human chorionic gonadotropin (hCG) in prepubertal mice during the periovulatory period. The localization of JAG1, the most abundantly expressed Notch ligand in the mouse ovary, underwent a striking shift from oocytes to somatic cells following hormone stimulation. The function of JAG1 in ovarian steroidogenic somatic cells was investigated using a long-term primary granulosa cell culture system. Disruption of Notch signaling using siRNA knockdown of Jag1 resulted in a suppression of granulosa cell differentiation into the steroidogenic phenotype and a retention of proliferative capacity. The loss of JAG1 led to a maintenance of MAPK/ERK and PI3K/AKT pathway activation, which are associated with proliferation in granulosa cells. These results indicate that the Notch signaling pathway can influence the broader signaling network in granulosa cells in complex way. During the highly dynamic periovulatory period, active Notch signaling favors the promotion of the mature steroidogenic preovulatory phenotype, at the expense of continued proliferation. Collectively, this thesis work describes a multi-faceted role of Notch signaling as a regulator of granulosa cell proliferation and differentiation throughout the gonadotropin independent and dependent stages of follicular development.
机译：卵泡是哺乳动物卵巢的功能单位，是一个紧密控制的微环境，其中的颗粒细胞可促进卵母细胞的生长和成熟。卵泡发育的早期事件是下丘脑-垂体-性腺轴的自主性，而是由在卵母细胞和体细胞之间双向通讯中使用的局部因素控制。青春期后，促性腺激素最终将成为卵泡生长，成熟和排卵的主要调节剂。人们越来越认识到，促性腺激素的作用是通过与局部卵巢内信号的相互作用来实现的。本论文探讨了一个这样的局部卵巢内调节剂，Notch信号通路，在卵巢卵泡发育的多个不同阶段的功能。； Notch通路是高度保守的细胞接触依赖性水杨酸信号系统，是原始卵泡形成的重要调节剂。在小鼠卵巢中。使用报告小鼠系鉴定Notch活性细胞，在属于促性腺激素独立和依赖发育阶段的卵泡颗粒细胞中观察到持续的Notch活性。基于此观察，我假设Notch信号通路在多个发育阶段调节独特的卵泡功能，从而促进卵泡的整体健康。在出生后一天（PND）的青春期前，颗粒细胞中活跃的Notch信号传导与更大的增殖能力有关。使用生殖细胞（J1KO）或受体的配体Jag1的条件敲除系进一步证实了Notch信号的促有丝分裂功能在PND19观察到颗粒细胞（N2KO）中的Notch2在卵巢中的增殖受到抑制。显着地扩展了在促性腺激素非依赖性卵泡生长阶段对Notch信号的理解，描述了在生长的卵泡中，Notch信号跨多层颗粒细胞传播的潜在机制。颗粒细胞中Notch信号的激活导致Jag1配体的表达增加，该Jag1配体可以激活邻近颗粒细胞上的Notch受体，这与横向诱导机制一致。; Notch活性以及卵巢中Notch配体和受体的表达均呈阳性在外排卵期被青春期前小鼠中的外源性人绒毛膜促性腺激素（hCG）激活LH受体后进行调节。 JAG1（在小鼠卵巢中表达最丰富的Notch配体）的定位在激素刺激后经历了从卵母细胞到体细胞的惊人转变。使用长期的初级颗粒细胞培养系统研究了JAG1在卵巢类固醇生成体细胞中的功能。使用Jag1的siRNA敲低来破坏Notch信号导致了颗粒细胞向类固醇生成型分化的抑制，并保留了增殖能力。 JAG1的丢失导致维持MAPK / ERK和PI3K / AKT途径的激活，这与颗粒细胞的增殖有关。这些结果表明Notch信号通路可以以复杂的方式影响颗粒细胞中更广泛的信号网络。在高度动态的排卵期，活跃的Notch信号有利于促进成熟的类固醇激素排卵前表型，但会持续增殖。总的来说，本论文工作描述了Notch信号传导在整个促性腺激素独立和依赖的卵泡发育阶段中作为颗粒细胞增殖和分化调节剂的多方面作用。

著录项

  • 作者

    Prasasya, Rexxi Diptya.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Molecular biology.;Cellular biology.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 329 p.
  • 总页数 329
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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