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

项目摘要 ERK（细胞外信号调节激酶）信号传导对女性生育力和正常胚胎发育至关重要 形态发生ERK信号传导调节以控制女性生育力的两个关键事件是：（a） 雌性减数分裂I和（B）卵母细胞减数分裂在长时间停滞后恢复（也称为卵母细胞减数分裂 成熟）。减数分裂I的常规执行需要同源染色体配对、排列、形成 物理连接，交换遗传信息，并将同源物分离成配子。调节不当 这些步骤中的任何一个都导致染色体分离失败，引起严重的发育障碍，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的进展，ERK的激活对于卵母细胞是必不可少的。 在减数分裂I中长时间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，这是一个对物种生殖健康至关重要的事件。减数分裂I然后恢复为卵母细胞 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协调的 和ERK激活。卵母细胞不能经历停滞或减数分裂成熟失败导致雌性 不育或出生缺陷。不适当的ERK信号转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磷酸化和调节的蛋白质介导这两个 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生殖的理解， 此外，还提供了有效的措施来调节干预途径。我们确定了两 作为ERK底物的蛋白RbAp 46和RbAp 48在减数分裂I期间调节染色体动力学， 卵母细胞减数分裂成熟。RbAp 46/RbAp 48是具有组蛋白功能的旁系同源蛋白 多梳抑制复合物2（PRC 2）和核小体重塑复合物（NuRD）中的伴侣蛋白 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） 它们通过ERK信号传导的调节和（ii）它们在调节雌性减数分裂I和卵母细胞成熟中的功能。的 这项建议的目的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.