The Role of Fzd9 in Hippocampal and Cortical Development

Fzd9 在海马和皮质发育中的作用

• 批准号: 7274419
• 负责人: JENNIFER L FREESE
• 金额: $ 5.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274419
• 关键词: Address; Adult; Alleles; Anatomy; Animals; Area; Autistic Disorder; Behavioral; Brain; Cell Count; Cell Death; Cell Lineage; Cell Survival; Cells; Characteristics; Child; Chromosome Deletion; Cognition; Condition; Cytoplasmic Granules; Defect; Deformity; Development; Disease; Disruption; Event; Exhibits; Genes; Genetic; Goals; Hippocampus (Brain); Human; Incidence; Knockout Mice; Laboratories; Language; Learning; Length; Medial; Memory; Morphogenesis; Morphology; Motor; Motor Cortex; Mus; Mutant Strains Mice; Mutation; Neocortex; Neurites; Neuroanatomy; Neurodevelopmental Disorder; Neurologic; Neurons; Numbers; Pathway interactions; Patients; Pattern; Performance; Personality; Phenotype; Play; Problem behavior; Process; Protein Overexpression; Range; Receptor Gene; Reporter; Research Proposals; Role; Seizures; Shapes; Signal Pathway; Signal Transduction; Simulate; Structure; Suggestion; Symptoms; Synapses; Syndrome; Testing; Transgenic Mice; Visual Cortex; Visuospatial; Week; Williams Syndrome; Work; clinically relevant; cohort; critical developmental period; dentate gyrus; design; developmental disease; gain of function; granule cell; loss of function; morris water maze; mutant; neocortical; neurodevelopment; neurogenesis; null mutation; pleasure; postnatal; precursor cell; receptor; recombinase; repaired; size; synaptogenesis; visual motor

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.

描述(申请人提供)：Frizzled9，一个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的高发生率。愉悦实验室的工作最近证明，Frizzled9基因突变的小鼠在齿状回存在发育缺陷，包括细胞过度死亡，导致齿状颗粒神经元数量略有减少。这些小鼠也有严重的视觉空间学习缺陷和癫痫阈值降低，这与威廉姆斯综合征患者的症状相似；因此，Frizzled9功能似乎在这种综合征中起着关键作用。WNTs在调节树突、轴突和突触的形态中起着重要的作用，Fzd9表达于海马区和新皮质的后部。因此，Fzd9转基因小鼠可能存在比已经证明的更广泛的缺陷。目前的研究方案将建立在之前对Fzd9功能的研究基础上，致力于回答三个问题：1.Frizzled9是否调节海马和皮质解剖？2.Frizzled9在成人大脑中具有功能吗？3.规范的Wnt信号是否调节齿状回中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Fzd9突变体中海马体和新皮质的详细细胞神经解剖学和连接性。此外，我将产生有条件的功能丧失和功能获得突变体，以研究Fzd9在发育和成年期中的作用。这可能表明，在突变小鼠中重新表达Fzd9成人基因可以修复由于Fzd9功能在发育过程中丧失而造成的部分行为缺陷。最后，我将研究Wnt过表达的影响，以更好地了解它在神经发育中的作用。Frizzled9是威廉姆斯综合征中缺失的大约20个基因之一；因此，了解它的功能对于识别它在这种疾病中的作用至关重要。这种神经发育障碍的特征是友善、热情洋溢的个性，语言能力增强，空间认知受损。由于在许多方面，这些患者保存最完好的功能正是自闭症患者受损最严重的，一些人认为，自闭症很可能从另一种重要的神经发育综合征中吸取了重要的教训。这些研究将有助于加深我们对这两种严重发育障碍的理解。