Iroquois function in the female reproductive tract

易洛魁人在女性生殖道中的功能

• 批准号: 10521759
• 负责人: Indrani C Bagchi
• 金额: $ 66.22万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521759
• 关键词: Ablation; Adult; Biology; Cell Communication; Cell Differentiation process; Cell Nucleus; Cells; Cytoplasm; Cytoskeletal Proteins; Cytoskeleton; Data; Decidual Cell; Decidual Cell Reactions; Defect; Development; Embryo; Embryo Deaths; Embryo Loss; Endometrial; Endothelium; Ensure; Event; Failure; Family; Female; Fertility; Gap Junctions; Genetic Transcription; Goals; Growth; Histology; Homeobox; Homeodomain Proteins; Investigation; Knock-out; Knockout Mice; Link; Mediating; Modeling; Molecular; Movement; Mus; Nuclear; Oocytes; Outcome; Ovarian; Ovary; Ovulation; Pattern; Phase; Phenotype; Placentation; Play; Pregnancy; Primordial Follicle; Proteins; Regulation; Role; Series; Signal Pathway; Signal Transduction; Site; Somatic Cell; Stains; Stromal Cells; System; Testing; Time; Transcriptional Regulation; Uterus; Vascularization; Work; base; beta catenin; cell motility; cell stroma; design; female fertility; granulosa cell; implantation; member; mouse model; mutant mouse model; ovarian reserve; premature; programs; protein function; public health relevance; pup; reproductive; reproductive tract; response; spatiotemporal; subfertility; transcription factor; trophoblast; vasculogenesis

Project summary/Abstract Two existential threats to female fertility include the premature loss of the ovarian reserve and early implantation/placentation failure. We recently discovered that Irx3 and Irx5, two of six members of the Iroquois homeobox (Irx) transcription factor family, show remarkable conservation of molecular and cellular actions associated with cognate cell-cell transitions critical for germline nest breakdown and primordial follicle formation (ovarian reserve) during ovary development and embryo-endometrial interactions leading to vasculogenesis during implantation and establishment of pregnancy. Previously, we employed a series of Irx3/5 mutant mouse models, including an Sf1-Cre/Flox strategy to highlight autonomous roles for Irx3 vs Irx5, especially in somatic cells. The fertility profiles for these mice also indicated that developmental expression of Irx3 contributes to the adult follicle’s response to external growth and ovulation signals and suggested that Irx3 has a critical role in oocyte integrity. AIM 1 is designed to discover the roles for Irx3 in the oocyte and uncover downstream targets and regulation profiles over time in ovary development. Ovarian histology and follicle counts identified oocyte deficits, but reproductive data suggested that other factors were also contributing to the subfertility phenotype in Irx3 knockout mice (Irx3 KO). Indeed, ablation of Irx3 in female mice resulted in a subfertile phenotype with fewer pups born in each litter. Our studies indicated a marked induction of Irx3 at the onset of decidualization and we observed a progressive loss of embryos starting at the decidual phase and extending through the end of pregnancy indicating a disrupted uterine response to the embryo that caused deficits in placentation. AIM 2 will test the hypothesis that Irx3 integrates stromal-endothelium and stromal-trophoblast interactions to ensure successful establishment of pregnancy. Finally, we observed punctate staining for IRX3 within cytoplasm of oocytes and uterine decidual cells. Based on our observations that IRX3 plays an important role in mediating cell-cell interactions, AIM 3 is designed to examine cytoplasmic signaling and localization of cytoskeletal machinery with respect to IRX3 presence. Altogether, our studies are designed to discover how Iroquois homeobox proteins mediate germline nest breakdown and primordial follicle formation to establish responsive follicles with healthy oocytes and decidualization that promotes a successful implantation and placentation program. Successful outcomes will increase our understanding of the biology that results in a healthy ovarian reserve and optimal uterine conditions for early embryo survival.

项目概要/摘要 对女性生育能力的两个生存威胁包括卵巢储备的过早丧失和 着床/胎盘形成失败。我们最近发现，Irx 3和Irx 5，六个成员中的两个， Iroquois同源盒（Irx）转录因子家族，在分子水平上具有显著的保守性， 与生殖细胞巢破裂关键的同源细胞-细胞转换相关的细胞活动， 原始卵泡形成（卵巢储备）在卵巢发育和胚胎-子宫内膜 在着床和妊娠建立期间导致血管发生的相互作用。在此之前， 我们采用了一系列Irx 3/5突变小鼠模型，包括Sf 1-Cre/Flox策略，以强调 Irx 3与Irx 5的自主作用，特别是在体细胞中。这些小鼠的生育能力也 表明Irx 3的发育表达有助于成年卵泡对外界刺激的反应， 生长和排卵信号，并表明Irx 3在卵母细胞完整性中具有关键作用。AIM 1是 旨在发现Irx 3在卵母细胞中的作用，并揭示下游靶点和调控 随着时间的推移，卵巢发育。卵巢组织学和卵泡计数确定卵母细胞缺陷， 但生殖数据表明，其他因素也有助于低生育力表型， Irx 3敲除小鼠（Irx 3 KO）。事实上，在雌性小鼠中去除Irx 3导致生育力低下的表型 每一窝出生的幼崽都更少。我们的研究表明，Irx 3在肿瘤发生时有明显的诱导作用。 蜕膜化，我们观察到胚胎从蜕膜期开始逐渐丢失， 持续到妊娠结束，表明子宫对胚胎的反应中断， 导致胎座形成的缺陷。AIM 2将检验Irx 3整合基质-内皮细胞的假设 和间质-滋养层相互作用，以确保成功建立妊娠。最后我们 在卵母细胞和子宫蜕膜细胞的细胞质中观察到IRX 3的点状染色。基于我们 观察到IRX 3在介导细胞-细胞相互作用中起重要作用，AIM 3被设计为 检查细胞质信号传导和相对于IRX 3存在的细胞骨架机器的定位。 总之，我们的研究旨在发现易洛魁人同源框蛋白如何介导生殖细胞巢 分解和原始卵泡形成，以建立具有健康卵母细胞的反应性卵泡， 促进成功着床和胎盘形成程序的蜕膜化。成功结果 将增加我们对健康卵巢储备和最佳卵巢储备的生物学的理解。 早期胚胎存活的子宫条件。