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

项目总结 ERK(细胞外信号调节激酶)信号对女性生育和正常胚胎至关重要 形态发生。ERK信号调节控制女性生育的两个关键事件是：(A) 雌性减数分裂I和(B)卵母细胞减数分裂在长时间停止后恢复(也称为卵母细胞减数分裂 成熟)。减数分裂的常规执行I需要同源染色体配对，对齐，形成 物理连接，交换遗传信息，并将同源基因分离成配子。监管不善 这些步骤中的任何一个都会导致染色体分离失败，导致严重的发育障碍，例如， 唐氏综合症。我们发现erk信号的丢失导致染色体不能维持突触。 导致胚胎死亡。除了减数分裂i进程外，ERK的激活对卵母细胞也是必不可少的。 减数分裂长期停滞后的发育和恢复I.卵母细胞在减数分裂I中停滞数十年 人类，这一事件对物种的生殖适合性至关重要。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是通过激素信号来协调的 和ERK激活。卵母细胞未能经历停滞或减数分裂成熟失败会导致雌性 不孕不育或出生缺陷。错误的ERK信号导致卵母细胞减数分裂成熟缺陷 不孕不育或出生缺陷。确定ERK磷酸化和调节以调节这两种蛋白的蛋白质 控制女性生育和胚胎形态发生的事件不仅将引导我们对女性的理解 而且还提供了有效的措施来调节干预的途径。我们确认了两个 RbAp46和RbAp48作为ERK底物调节减数分裂I和 卵母细胞减数分裂成熟。RbAp46/RbAp48是与组蛋白功能相似的蛋白质 多梳抑制复合体2(PRC2)和核小体重塑复合体(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，这是第一次描述(I) 它们受ERK信号的调节；(Ii)它们在调节雌性减数分裂I和卵母细胞成熟中的作用。这个 这项建议的目标是了解这些功能的遗传和分子基础。

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.