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

• 批准号: 7628713
• 负责人: CHRISTOPHER C WYLIE
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-27 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628713
• 关键词: 3' Untranslated Regions; Affect; Attenuated; Axon; Binding Sites; Biochemical; Biological; Biological Neural Networks; Brain; Data; Dendrites; Development; Epilepsy; FMR1; Fluorescent in Situ Hybridization; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Translation; Germ Cells; Glutamates; Goals; Growth Cones; Hippocampal Mossy Fibers; Hippocampus (Brain); Immunofluorescence Immunologic; Impairment; Inherited; Ions; Knock-out; Knockout Mice; Knowledge; Lead; Ligands; MAP1 Microtubule-Associated Protein; Mediating; Mental Retardation; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Neonatal; Neurons; Patients; Polyribosomes; Predisposition; Protein Binding; Protein Biosynthesis; Protein Deficiency; Proteins; Psyche structure; RNA-Binding Proteins; Regulation; Reporting; Repression; Role; Seizures; Semaphorin-3A; Stem Cell Factor; Stimulus; Synapses; Synaptic plasticity; Syndrome; Testing; Translational Regulation; Translations; Work; axon growth; axonal guidance; axonal sprouting; cell behavior; cell motility; in vivo; insight; metabotropic glutamate receptor type 1; microtubule-associated protein 1B; mossy fiber; neuron development; reconstruction; response

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。