Cell Cycle Control in Early Drosophila Development

描述（由申请人提供）：发育的开始需要受精卵细胞周期的重新启动。其先决条件是减数分裂的完成，用于产生单倍体卵子和精子的细胞周期的改变，以及精子和卵子融合导致的受精卵中DNA复制和有丝分裂的激活。减数分裂细胞周期在卵子发生中受到发育控制，具有特定的阻滞和释放点以允许卵母细胞分化以及减数分裂完成和受精之间的协调。在许多生物体中，快速胚胎发生是通过依赖于母体储备的修改的细胞周期并且在没有转录和生长的情况下发生而实现的。这些发育策略强调了转录后调控的要求：转录激活母体mRNA库以及完成减数分裂的受调控蛋白水解，以及驱动胚胎分裂周期的翻译调控。果蝇是一种理想的模式生物，在其中确定的关键调控机制和基因的翻译和蛋白水解控制的减数分裂和早期胚胎周期。优秀的遗传学和细胞生物学方法允许鉴定和诊断这些细胞周期中有缺陷的突变体，并且控制基因通常在人类中是保守的。因此，这些研究将为导致出生缺陷，不孕不育和癌症的监管缺陷提供基本见解。减数分裂细胞周期的调控基因将通过克隆在减数分裂发育控制失败的突变体集合中受影响的基因来恢复，并且基因组学筛选将鉴定随着卵母细胞进入减数分裂和完成减数分裂而被激活的mRNA。后期促进复合物/环体的减数分裂形式APC/CCort控制卵中完成减数分裂所必需的蛋白水解。APC/CCort的特异性将进行研究，从已经分离的显性抑制因子中鉴定底物和调节剂。PAN GU（PNG）蛋白激酶复合物通过促进细胞周期蛋白B的翻译以驱动有丝分裂来调节早期胚胎周期。PNG还通过促进SMAUG（SMG）的翻译（其触发母体mRNA的降解）来控制胚胎发生后期从母体到合子控制发育的过渡。PNG激酶的发育调控将被破译，其促进翻译的机制将被定义，特别是其与翻译阻遏物PUM（PUM）的关系。将分离PNG和相互作用蛋白的其他靶标。 公共卫生相关性：当精子和卵子在受精时融合时，发育开始，导致卵子中减数分裂的完成和新形成的胚胎中细胞分裂的开始。出生缺陷和不育是由于未能正确调节减数分裂和胚胎细胞分裂。我们的研究将确定新的调节蛋白质的正确控制减数分裂和发展的开始。

DESCRIPTION (provided by applicant): The onset of development requires the restart of the cell cycle in the fertilized egg. The prerequisites for this are the completion of meiosis, the modified cell cycle used to produce haploid eggs and sperm, and the activation of DNA replication and mitosis in the zygote that results from fusion of sperm and egg. The meiotic cell cycle is under developmental control in oogenesis, with specific arrest and release points to permit oocyte differentiation and coordination between completion of meiosis and fertilization. In many organisms, rapid embryogenesis is made possible by a modified cell cycle that relies on maternal stockpiles and occurs in the absence of transcription and growth. These developmental strategies highlight the requirement for post-transcriptional regulation: translational activation of maternal pools of mRNAs as well as regulated proteolysis for the completion of meiosis, and translational regulation to drive the embryonic division cycles. Drosophila is an ideal model organism in which to identify the key regulatory mechanisms and genes that govern translational and proteolytic control of the meiotic and early embryonic cycles. Superb genetic and cell biological approaches permit identification and diagnosis of mutants defective in these cell cycles, and control genes most often are conserved in humans. Thus these studies will provide fundamental insights into regulatory defects leading to birth defects, infertility and cancer. Regulatory genes for the meiotic cell cycle will be recovered by cloning the genes affected in a collection of mutants with failures in the developmental control of meiosis, and a genomics screen will identify mRNAs translationally activated as oocytes progress into meiosis and complete meiosis. A meiotic form of the Anaphase Promoting Complex/Cyclosome, APC/CCort, controls proteolysis essential for the completion of meiosis in the egg. The specificity of APC/CCort will be investigated, with the identification of substrates and regulators from dominant suppressors that already have been isolated. The PAN GU (PNG) protein kinase complex regulates the early embryonic cycles by promoting translation of Cyclin B to drive mitosis. PNG also controls the transition from maternal to zygotic control of development later in embryogenesis by promoting the translation of SMAUG (SMG), which triggers the degradation of maternal mRNAs. The developmental regulation of PNG kinase will be deciphered, and the mechanism by which it promotes translation will be defined, particularly its relationship to the translational repressor PUMILIO (PUM). Additional targets of PNG and interacting proteins will be isolated. PUBLIC HEALTH RELEVANCE: Development begins when sperm and egg fuse at fertilization, causing the completion of meiosis in the egg and the onset of cell division in the newly formed embryo. Birth defects and infertility result from failure to properly regulate meiosis and embryonic cell division. Our research will identify new regulatory proteins essential for the proper control of meiosis and the onset of development.