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

• 批准号: 10219320
• 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
• 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/10219320
• 关键词: Alleles; Apoptosis; Biochemical Genetics; 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; Human; Image; In Vitro; Infertility; Intervention; Knowledge; Lead; Link; Lobular Neoplasia; MAPK1 gene; Maintenance; Mammals; Mass Spectrum Analysis; Measures; Mediating; Meiosis; Methylation; Microscopy; Modeling; Molecular; Molecular Chaperones; Morphogenesis; Nuclear; Nuclear Envelope; Nuclear Pore; Nuclear Pore Complex; Oocytes; Pachytene Stage; Pathway interactions; Phenotype; Phospho-Specific Antibodies; Phosphorylation; Polycomb; Pore Proteins; Process; Proteins; RNA; RNA Interference; Regulation; Reproduction; Research; Resolution; Role; Signal Pathway; Signal Transduction; Sterility; Synaptonemal Complex; Testing; Time; base; 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; transcriptome sequencing

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.

项目摘要 ERK（细胞外信号调节激酶）信号传导对于女性生育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能力的两个关键事件是（a） 女性减数分裂I和（b）长时间逮捕后恢复卵母细胞减数分裂（也称为卵母细胞减数分裂 成熟）。减数分裂的定型执行我要求同源染色体对，对齐，形式 物理连接，交换遗传信息并将同源物隔离为游戏。错误调节 这些步骤中的任何一项导致染色体隔离失败，导致严重发育障碍，例如 唐氏综合症。我们发现ERK信号传导的损失导致染色体失败无法保持突触 引起胚胎致死性。除减数分裂I的进展外，ERK激活对于卵母细胞至关重要 长期停止减数分裂I.卵母细胞逮捕数十年后， 人类，这对于该物种的生殖适应性至关重要。减数分裂，然后恢复为卵母细胞 成熟和卵母细胞减数分裂恢复或成熟的过程通过荷尔蒙信号进行协调 和ERK激活。卵母细胞未能被捕或减数分裂成熟导致雌性失败 不育或出生缺陷。不适当的ERK信号导致卵母细胞减数分裂成熟导致缺陷 不育或出生缺陷。确定ERK磷酸化和调节以介导这两种的蛋白质 控制女性生育能力和胚胎形态发生的事件不仅指导我们对女性的理解 繁殖，但还提供了有效的措施来调节干预措施的途径。我们确定了两个 蛋白RBAP46和RBAP48作为ERK底物，在减数分裂I和 卵母细胞减数分裂成熟。 RBAP46/RBAP48是寄生虫蛋白，起作用 Polycomb抑制复合物2（PRC2）和核小体重塑络合物（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信号传导和（ii）控制女性减数分裂I和卵母细胞成熟的功能。这 该建议的目标是了解这些功能的遗传和分子基础。