Developmentally sensitive regulatory mechanisms of synapse assembly and function

据估计，超过6%的美国人（或近1900万人）患有严重的精神障碍。许多这类疾病出现在发育或青春期，强有力的证据支持它们是由基因突变或基因拷贝数变化引起或加剧的。治疗方法是有的，但治愈的方法很少。人类遗传学研究已经确定CYFIP 1是一种在多种发育性脑疾病中失调的基因，包括某些形式的Angelman和Prader-Willi综合征，自闭症谱系障碍和精神分裂症。一个基因是如何导致如此多的疾病的？ CYFIP 1产生一种细胞质蛋白，即细胞质FMRP相互作用蛋白（Cyfip 1），具有两种独立且高度保守的功能。Cyfip 1作为非经典起始因子4 E结合蛋白（4 E-BP）抑制FMRP靶mRNA的帽依赖性翻译，并且作为WAVE复合物的组成部分调节质膜上分支肌动蛋白丝的产生。已知帽依赖性翻译和肌动蛋白细胞骨架的调节对于突触组装、形态和可塑性是重要的，并且也已知是易受发育性脑障碍影响的途径。因此，很容易理解为什么即使是Cyfip 1的一个拷贝的丢失也会产生广泛的后果，但是Cyfip 1在发育突触中的功能还没有得到很好的理解。在这个建议中，我们将研究Cyfip 1如何有助于突触的发展，功能和可塑性，使用我们开发的小鼠模型表达降低水平的Cyfip 1。初步实验表明，Cyfip 1水平降低的神经元在发育过程中表现出强烈的，主要是突触前表型，这在青春期是缺失的，并且在青春期表现出同样强烈的，但突触后表型，这在年轻动物中是缺失的。基于这些发现，我们将测试的假设，Cyfip 1的行动，帽依赖性蛋白质合成和肌动蛋白聚合有助于差异突触前功能在发展和突触后生理和可塑性成熟。

DESCRIPTION (provided by applicant): It is estimated than more 6% of all Americans (or nearly 19 million individuals) suffer from a serious mental disorder. Many such disorders arise during development or adolescence, and strong evidence supports that they are caused or exacerbated by gene mutations or variations in gene copy number. Treatments exist, but there are few cures. Human genetic studies have identified CYFIP1 as a gene that is dysregulated in a wide variety of developmental brain disorders including certain forms of Angelman and Prader-Willi syndromes, autism spectrum disorders, and schizophrenia. How does a single gene contribute to so many disorders? CYFIP1 produces a cytoplasmic protein, cytoplasmic FMRP interacting protein (Cyfip1), having two independent and highly conserved functions. Cyfip1 represses cap-dependent translation of FMRP target mRNAs as a noncanonical initiation factor 4E binding protein (4E-BP), and it regulates the generation of branched actin filaments at the plasmalemma as an integral component of the WAVE complex. Regulation of both cap-dependent translation and actin cytoskeleton are known to be important for synapse assembly, morphology, and plasticity and are also known to be pathways that are vulnerable to developmental brain disorders. Thus it is easy to appreciate why loss of even a single copy of Cyfip1 could have broad consequences, but the function of Cyfip1 at developing synapses is not well understood. In this proposal we will investigate how Cyfip1 contributes to synapse development, function, and plasticity using a mouse model we developed expressing reduced levels of Cyfip1. Preliminary experiments show that neurons with reduced Cyfip1 levels display a strong, principally presynaptic phenotype during development that is missing in adolescence, and an equally strong, but postsynaptic phenotype in adolescence that is missing in younger animals. Based on these findings, we will test the hypothesis that Cyfip1's actions in cap-dependent protein synthesis and actin polymerization contribute differentially to presynaptic function during development and postsynaptic physiology and plasticity in maturity.