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The Roles of Steel Factor in Germ Cell Behavior in the Mouse

钢因子在小鼠生殖细胞行为中的作用

基本信息

批准号：
7900901
负责人：
CHRISTOPHER C WYLIE
金额：
$ 37.3万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-27 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900901
关键词：
Alternative Splicing Antibodies Appearance Axon Behavior Behavior Control Binding Biochemical Biological Assay Brain Cell Count Cell Proliferation Cell Survival Cell surface Cells Cleaved cell Congenital Abnormality Coupled Data Dendrites Development Embryo Endoderm Epilepsy FMR1 Fibrinogen Fragile X Syndrome Future Gastrula Genetic Translation Germ Cells Germ Lines Glutamates Goals Gonadal structure Growth Cones Hippocampal Mossy Fibers Homing Homing Behavior Imagery Immigration Impairment Inherited Interleukin-3 Ions Lead Life Ligands Location MAP1 Microtubule-Associated Protein Mediating Membrane Membrane Proteins Mental Retardation Messenger RNA MicroRNAs Modeling Molecular Mus Nature Neurons Organ Paper Pathway interactions Pattern Play Polyribosomes Population Primordium Property Protein Binding Protein Biosynthesis Protein Deficiency Proteins Proto-Oncogene Protein c-kit Psyche structure Public Health Receptor Protein-Tyrosine Kinases Reporter Role Signal Transduction Site Source Staging Staining method Stains Steel Stem Cell Factor Stem cells Sterility Structure of primordial sex cell Synaptic plasticity Syndrome Testing Time Tissues Translations Travel White Spots Work allantois base cell behavior cell motility design embryo tissue loss of function migration movie neuron development novel pluripotency receptor research study response stem cell population tumor

项目摘要

The frag ile X mental re tardation protein (FMRP) binds mRNA and micro RNA, is associated with polyribosomes, and is localized in dendrites and axons. Hence, FMRP is thought to reg ulate the local translation of its mRNA targets as a means to influence neuronal development and plasticity. The lack of FMRP resu lts in dysregulated protein synthesis, wh ich is an underlying pathomechanism for the deficits in synaptic plasticity and mental impairment in frag ile X syndrome. Our long term -goal is to elucidate how FMRP controls mRNA translation and local protein synthesis du ring normal neuronal development and how FMRP deficiency leads to fragile X syndrome, the most common form of inherited mental retardation. A decade of extensive studies have characterized the biochemical interactions between FMRP and its mRNA ligands. In fact, more than 400 mRNAs have been found to associate with FMRP. However, the molecular mechanims by wh ich FMRP controls translat ion of its mRNA targets are st ill poorly understood. Moreover, how dysregulated translation , as a result of FMRP deficiency, may lead to aberrant neuronal development in the frag ile X brain remains unknown. Several lines of evidence, including our previous work, suggest that the mRNA encoding microtubule associated protein 1 B (MAP1 B) is a funct ional target of FMRP, and the lack of FMRP resu lts in dysregulated MAP1 B translation in Fmr1 KO neurons. The goal of th is proposal is to use MAP1 B as a model target of FMRP to delineate molecular mechanisms for FMRP to regulate protein synthesis in response to neuronal activation and the functional importance of FMRP-dependent trans lational regulat ion in neuronal development. Two specific aims are proposed : 1) To del ineate how FMRP-dependent local translation of MAP1 B may control growth cone dynamics in repsonse to an axon gu idance factor and activation of group 1 metabotropic glutamate recepto r; 2) To determine whether and how FMRP-mediated translat ional regu lation of MAP1 B governs projections of hippocampal mossy fiber axons during normal development and in epilepsy.

脆性X智力低下蛋白（FMRP）结合mRNA和microRNA，与多聚核糖体，并定位于树突和轴突中。因此，FMRP被认为是调节当地的其mRNA靶点的翻译作为影响神经元发育和可塑性的手段。缺乏 FMRP导致蛋白质合成失调，这是FMRP缺陷的潜在病理机制。脆性X综合征突触可塑性和智力损害我们的长期目标是阐明 FMRP在正常神经元发育过程中控制mRNA翻译和局部蛋白质合成及其机制 FMRP缺乏会导致脆性X综合征，这是遗传性智力低下的最常见形式。一近十年来的广泛研究已经确定了FMRP及其mRNA之间的生物化学相互作用配体。事实上，已经发现超过400种mRNA与FMRP相关。然而，分子 FMRP控制其mRNA靶点表达的机制仍然知之甚少。此外，委员会认为，由于FMRP缺乏，翻译失调如何导致神经元发育异常， X染色体碎片的大脑仍然未知。几条证据，包括我们以前的工作，表明编码微管相关蛋白1 B（MAP 1 B）的mRNA是FMRP的功能靶点， FMRP导致Fmr 1 KO神经元中MAP 1 B翻译失调。该提案的目的是利用 MAP 1 B作为FMRP的模型靶点探讨FMRP调控蛋白质的分子机制神经元激活引起的FMRP依赖性翻译的功能重要性调节神经元发育。提出了两个具体的目标：1）界定如何FMRP依赖 MAP 1 B的局部翻译可能响应轴突导向因子而控制生长锥动力学，第1组代谢型谷氨酸受体的激活; 2）为了确定是否以及如何FMRP介导 MAP 1 B的神经调节作用对正常海马苔藓纤维轴突投射的影响发展和癫痫。