The role of local mRNA translation in the regulation of dendritic spine morphogenesis

智力迟钝和自闭症是一种非常普遍和多样化的疾病，目前尚无有效的治疗方法。这些疾病的一个共同特征是来自受影响患者的神经细胞表现出形状异常的树突棘，树突棘是形成突触的结构。神经发育疾病研究中的一个关键问题是：是什么原因导致这些疾病的脊柱形态异常？最近，在细胞内特定靶点的蛋白质合成（“局部翻译”）已经成为一种涉及细胞形状和功能控制的基因调控新机制。在脆性X综合征（FXS）中，这一机制受损，这是遗传性智力迟钝最常见的形式。因此，本项目主要围绕两个问题来探讨局部翻译在脊柱形状调节中的作用：(1)树突棘的形状是否受特定调节蛋白（RhoA）的局部翻译控制？(2) FXS中这一特异性调控是否受损，从而导致脊柱形状异常？综上所述，该项目可能阐明树突棘形状控制的新机制，并可能提供FXS遗传缺陷与神经解剖学异常之间的联系。因为树突棘形状的调节对许多精神疾病以及学习和记忆等生理过程都有影响，所以这个项目可能会对我们对大脑功能的理解产生普遍影响。

Mental retardation and autism are a highly prevalent and diverse group of disorders for which there is no effective treatment. A common feature of these diseases is that nerve cells from affected patients exhibit abnormally-shaped dendritic spines, structures that serve to form synapses. A critical question in neurodevelopmental disease research is: what causes the abnormal spine morphology in these diseases? Recently, the synthesis of proteins at specific target sites within a cell (“local translation”) has emerged as a novel mechanism for gene regulation that is involved in the control of cell shape and function. In Fragile X syndrome (FXS), the most common form of inherited mental retardation, this mechanism is impaired. Thus, the present project focuses on two questions to explore the role of local translation in the regulation of spine shape: (1) Is the shape of dendritic spines controled by the local translation of a specific regulatory potein (RhoA)? (2) Is this specific regulation impaired in FXS and, thereby, leads to abnormally-shaped spines? In summary, this project might elucidate a novel mechanism for the control of dendritic spine shape and may provide a link between the genetic deficit and the neuroanatomical abnormalities in FXS. Because the regulation of dendritic spine shape has implications for many mental diseases as well as for physiological processes like learning and memory, this project might have a general impact on our understanding of brain function.