The Role of Fzd9 in Hippocampal and Cortical Development

描述（由申请方提供）：Frizzled 9是一种Wnt受体基因，在人类威廉姆斯综合征的染色体缺失区间内。这种疾病的症状包括视觉空间处理缺陷和癫痫发作的高发病率。Pleasure实验室最近的工作表明，Frizzled 9突变的小鼠在齿状回中存在发育缺陷，包括导致齿状颗粒神经元数量少量减少的过度细胞死亡。这些小鼠还具有严重的视觉空间学习缺陷和降低的癫痫发作阈值，模仿威廉姆斯综合征患者的症状;因此，Frizzled 9功能似乎在该综合征中至关重要。Wnt在调节树突、轴突和突触形态中具有重要作用，并且Fzd 9在整个海马和后部新皮质中表达。因此，Fzd 9转基因小鼠可能具有比已经证明的更广泛的缺陷。目前的研究计划将建立在Fzd 9功能的先前研究的基础上，致力于回答三个问题：1。Frizzled 9是否调节海马和皮质解剖结构？2. Frizzled 9在成人大脑中有功能吗？和3.经典Wnt信号是否调节齿状回未成熟神经元的形态分化或存活？为了实现这些目标，我将研究Fzd 9突变体中海马和新皮层的详细细胞神经解剖学和连接。此外，我将产生条件性功能丧失和功能获得突变体，以研究Fzd 9在发育和成年期间的作用。这可能表明，突变小鼠中Fzd 9的成年再表达可以挽救由于发育期间Fzd 9功能丧失而导致的一些行为缺陷。最后，我将研究Wnt过表达的影响，以更好地了解其在神经发育中的作用。Frizzled 9是威廉姆斯综合征中缺失的大约20个基因之一;因此，了解其功能对于辨别其在这种情况下的作用至关重要。这种神经发育障碍的特点是友好，热情洋溢的个性，增强的语言能力和受损的空间认知。由于在许多方面，这些患者中保存最完好的功能恰恰是自闭症患者中受损最严重的功能，因此有人认为，自闭症可能会从这种重要的神经发育综合征中学到重要的教训。这些研究将有助于我们进一步了解这两种重要的发育障碍。

DESCRIPTION (provided by applicant): Frizzled9, a Wnt receptor gene, is within the chromosomal deletion interval for Williams syndrome in humans. Symptoms of this disease include visuospatial processing defects and a high incidence of seizures. Work from the Pleasure laboratory has recently demonstrated that mice with mutations in Frizzled9 have developmental defects in the dentate gyrus, including excess cell death that result in a small decrease in the number of dentate granule neurons. These mice also have profound visualspatial learning deficits and lowered seizure threshold, mimicking symptoms of Williams Syndrome patients; hence, it seems likely that Frizzled9 function is critical in this syndrome. Wnts have important roles in regulating dendritic, axonal, and synaptic morphology, and Fzd9 is expressed throughout the hippocampus and posterior neocortex. Hence, Fzd9 transgenic mice may have more widespread defects than has already been demonstrated. The current research proposal will build on the previous studies of Fzd9 function by working toward answering three questions: 1. Does Frizzled9 regulate hippocampal and cortical anatomy? 2. Does Frizzled9 have functions in the adult brain? and 3. Does canonical Wnt signaling regulate the morphological differentiation or survival of immature neurons in the dentate gyrus? To accomplish these goal I will examine the detailed cellular neuroanatomy and connectivity of the hippocampus and neocortex in Fzd9 mutants. In addition, I will generate conditional loss-of-function and gain-of-function mutants to examine the role of Fzd9 during development and in adulthood. This may demonstrate that adult re-expression of Fzd9 in mutant mice can rescue some of the behavioral deficits due to a loss of Fzd9 function during development. Finally, I will investigate the effects of Wnt overexpression to better understand its role in neurodevelopment. Frizzled9 is one of approximately 20 genes deleted in Williams syndrome; therefore, understanding its function is critical to discerning its role in this condition. This neurodevelopmental disorder is characterized by a friendly, effusive personality, enhanced language ability and impaired spatial cognition. Since in many ways the most preserved functions in these patients are the exact ones most impaired in autistic patients, some have suggested that there are likely to be important lessons for autism to be learned from this other important neurodevelopmental syndrome. These studies will help to further our understanding of both of these significant developmental disorders.