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

脆性X精神反应蛋白(FMRP)结合mRNA和Micro RNA，与 多聚核糖体，定位于树突和轴突。因此，FMRP被认为调整了当地的 其信使核糖核酸靶标的翻译作为影响神经元发育和可塑性的手段。缺乏 FMRP导致蛋白质合成异常，这是导致血管紧张素转换酶缺陷的潜在病理机制。 脆性X综合征的突触可塑性和智能障碍。我们的长期目标是阐明 FMRP控制正常神经元发育过程中的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，这是最常见的遗传性智力低下形式。一个 十年的广泛研究已经表征了FMRP及其mRNA之间的生化相互作用 配基。事实上，已发现400多个mRNAs与FMRP有关。然而，分子 FMRP控制其信使核糖核酸靶向翻译的机制尚不清楚。此外， FMRP缺乏所致的翻译失调如何导致脑内神经元发育异常 脆弱的X大脑仍然未知。有几条证据，包括我们之前的工作，表明 编码微管相关蛋白1B(MAP1B)的mRNA是FMRP的一个功能靶点，而缺乏 FMRP导致Fmr1KO神经元MAP1B翻译异常。这项提议的目标是使用 MAP1B作为FMRP的模型靶点研究FMRP调控蛋白质的分子机制 神经元激活反应的合成及FMRP依赖的转录物的功能重要性 神经元发育的调控。提出了两个具体目标：1)确定FMRP是如何依赖的 MAP1B的局部翻译可能控制生长锥动力学，使之成为轴突GU阻抗因子 激活第1组代谢性谷氨酸受体r；2)以确定FMRP是否以及如何介导 正常情况下MAP1B的翻译调节调控海马苔藓纤维轴突的投射 在发育和癫痫方面。

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.