Cell Cycle Control in Early Drosophila Development

果蝇早期发育中的细胞周期控制

• 批准号: 8292103
• 负责人: Terry L. ORR-WEAVER
• 金额: $ 40.54万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292103
• 关键词: Affect; Amphibia; Animal Model; Biological; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Collection; Complex; Congenital Abnormality; Cues; Cyclin B; DNA biosynthesis; Defect; Development; Diagnosis; Drosophila genus; Embryo; Embryonic Development; Failure; Fertilization; Funding; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Haploidy; Human; Infertility; Insecta; Malignant Neoplasms; Maternal Messenger RNA; Mediating; Meiosis; Messenger RNA; Mitosis; Oocytes; Oogenesis; Organism; Phosphotransferases; Polyadenylation; Post-Transcriptional Regulation; Protein Kinase; Proteins; Proteolysis; Regulation; Regulator Genes; Research; Specificity; Translating; Translational Activation; Translational Regulation; Translations; anaphase-promoting complex; blastomere structure; egg; gene cloning; genetic regulatory protein; insight; marine organism; mutant; oocyte maturation; public health relevance; sperm cell; zygote

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.

描述（由申请人提供）：发育的开始需要受精卵中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修改的细胞周期，以及由精子和卵子融合产生的受精卵中 DNA 复制和有丝分裂的激活。减数分裂细胞周期在卵子发生过程中处于发育控制之下，具有特定的停滞和释放点，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修改细胞周期来实现的，该细胞周期依赖于母体储存，并且在没有转录和生长的情况下发生。这些发育策略强调了转录后调节的需求：母体 mRNA 库的翻译激活以及用于完成减数分裂的受调节蛋白水解，以及驱动胚胎分裂周期的翻译调节。果蝇是一种理想的模式生物，可用于识别控制减数分裂和早期胚胎周期的翻译和蛋白水解控制的关键调控机制和基因。精湛的遗传和细胞生物学方法可以识别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保守。因此，这些研究将为导致出生缺陷、不孕症和癌症的监管缺陷提供基本见解。减数分裂细胞周期的调节基因将通过克隆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当卵母细胞进入减数分裂和完全减数分裂时翻译激活的mRNA。减数分裂后期促进复合物/环体 (APC/CCort) 控制着卵子减数分裂完成所必需的蛋白水解作用。将研究 APC/CCort 的特异性，从已分离的显性抑制因子中鉴定底物和调节因子。 PAN GU (PNG) 蛋白激酶复合物通过促进细胞周期蛋白 B 的翻译来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（触发母体 mRNA 的降解）来控制胚胎发生后期从母体发育到合子发育控制的转变。 PNG激酶的发育调控将被破译，并且其促进翻译的机制将被定义，特别是它与翻译抑制子PUMILIO (PUM)的关系。 PNG 和相互作用蛋白的其他靶标将被分离。 公共卫生相关性：当精子和卵子在受精时融合，导致卵子减数分裂完成并在新形成的胚胎中开始细胞分裂时，发育就开始了。出生缺陷和不孕症是由于未能正确调节减数分裂和胚胎细胞分裂造成的。我们的研究将确定对减数分裂和发育开始的适当控制至关重要的新调节蛋白。