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ERK mediated regulation of RbAp46/48 during female germ cell development

ERK 介导的雌性生殖细胞发育过程中 RbAp46/48 的调节

基本信息

批准号：
10612853
负责人：
Swathi Arur
金额：
$ 32.66万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612853
关键词：
Alleles Apoptosis Biochemical Biological Assay Biological Models CRISPR/Cas technology Caenorhabditis elegans Chromosome Pairing Chromosome Segregation Chromosomes Complex Confocal Microscopy Congenital Abnormality Coupled Defect Development Down Syndrome Dynein ATPase Embryo Embryonic Development Epigenetic Process Event Extracellular Protein Extracellular Signal Regulated Kinases Failure Female Female sterility Fertility Gene Expression Gene Silencing Genetic Genetic Models Germ Cells Goals Gonadal structure Histone H3 Histones Homologous Gene Human Image In Vitro Infertility Intervention Knowledge Link Lobular Neoplasia MAPK1 gene Maintenance Mammals Mass Spectrum Analysis Measures Mediating Meiosis Methylation Modeling Molecular Molecular Chaperones Morphogenesis Nuclear Nuclear Envelope Nuclear Pore Nuclear Pore Complex Oocytes Pachytene Stage Pathway interactions Phenotype Phospho-Specific Antibodies Phosphorylation Phosphorylation Inhibition Polycomb Pore Proteins Process Proteins RNA RNA Interference Regulation Reproduction Research Role Signal Pathway Signal Transduction Sterility Synaptonemal Complex Testing Time developmental disease epigenetic silencing female fertility gain of function gene repression genetic analysis genetic information hormonal signals loss of function member mimetics mutant oocyte maturation protein function reproductive fitness segregation superresolution microscopy transcriptome sequencing

项目摘要

PROJECT SUMMARY ERK (Extracellular signal Regulated Kinase) signaling is critical for female fertility and normal embryonic morphogenesis. Two key events that ERK signaling regulates to control female fertility are (a) progression of female meiosis I and (b) resumption of oocyte meiosis after prolonged arrest (also called oocyte meiotic maturation). Stereotypical execution of meiosis I requires that homologous chromosomes pair, align, form physical connections, exchange genetic information and segregate homologs into gametes. Mis-regulation of any of these steps results in failures in chromosome segregation causing severe developmental disorders, e.g., the Down’s syndrome. We find that loss of erk signaling results in failure of chromosomes to maintain synapsis causing embryonic lethality. In addition to meiosis I progression, ERK activation is essential for oocyte development and resumption after prolonged arrest in meiosis I. Oocytes arrest in meiosis I for decades in humans, an event that is critical for reproductive fitness of the species. Meiosis I is then resumed as the oocyte matures and the process of oocyte meiotic resumption or maturation is coordinated through hormonal signaling and ERK activation. Failure of oocytes to either undergo arrest or fail in meiotic maturation results in female sterility or birth defects. Inappropriate ERK signaling results in defects in oocyte meiotic maturation causing sterility or birth defects. Determining the proteins that ERK phosphorylates and regulates to mediate these two events that control female fertility and embryonic morphogenesis will guide not only our understanding of female reproduction but also provide effective measures to modulate the pathway for interventions. We identified two proteins RbAp46 and RbAp48 as ERK substrates that regulate chromosome dynamics during meiosis I and oocyte meiotic maturation respectively. RbAp46/RbAp48 are paralogous proteins that function as histone chaperones in the Polycomb Repressive Complex 2 (PRC2) and Nucelosome Remodeling Complex (NuRD) in worms and mammals to regulate epigenetic marks and transcriptional silencing, this is the first description of (i) their regulation by ERK signaling and (ii) their function in regulating female meiosis I and oocyte maturation. The goal of this proposal is to understand the genetic and molecular basis of these functions.

项目概要 ERK（细胞外信号调节激酶）信号对于女性生育能力和正常胚胎至关重要形态发生。 ERK 信号调节以控制女性生育力的两个关键事件是 (a) 女性减数分裂 I 和 (b) 长期停滞后卵母细胞减数分裂的恢复（也称为卵母细胞减数分裂）成熟）。减数分裂 I 的典型执行需要同源染色体配对、对齐、形成物理连接、交换遗传信息并将同源物分离成配子。监管不当这些步骤中的任何一个都会导致染色体分离失败，从而导致严重的发育障碍，例如，唐氏综合症。我们发现 erk 信号传导的丧失会导致染色体无法维持突触造成胚胎致死。除了减数分裂 I 的进展外，ERK 激活对于卵母细胞也至关重要减数分裂 I 长期停滞后的发育和恢复。卵母细胞在减数分裂 I 中停滞数十年人类，这一事件对于物种的繁殖适应性至关重要。然后减数分裂 I 恢复为卵母细胞成熟，卵母细胞减数分裂恢复或成熟的过程通过激素信号传导进行协调和 ERK 激活。卵母细胞未能停滞或减数分裂成熟失败会导致雌性不育或出生缺陷。不适当的 ERK 信号传导导致卵母细胞减数分裂成熟缺陷不育或出生缺陷。确定 ERK 磷酸化和调节以介导这两种蛋白的蛋白质控制女性生育力和胚胎形态发生的事件不仅将指导我们对女性的理解生殖，还提供有效措施来调节干预途径。我们确定了两个蛋白质 RbAp46 和 RbAp48 作为 ERK 底物，在减数分裂 I 和卵母细胞分别减数分裂成熟。 RbAp46/RbAp48 是具有组蛋白功能的旁系同源蛋白多梳抑制复合物 2 (PRC2) 和核小体重塑复合物 (NuRD) 中的伴侣蠕虫和哺乳动物调节表观遗传标记和转录沉默，这是 (i) 的第一个描述它们通过 ERK 信号传导进行调节，以及 (ii) 它们在调节女性减数分裂 I 和卵母细胞成熟中的功能。这该提案的目标是了解这些功能的遗传和分子基础。