Dishevelled-Mediated Control of Wnt/PCP Pathways

Wnt/PCP 通路的凌乱介导的控制

• 批准号: 8739102
• 负责人: ANTHONY J. WYNSHAW-BORIS
• 金额: $ 36.52万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739102
• 关键词: Dishevelled; Mediated; Control; Wnt; PCP

DESCRIPTION (provided by applicant): The well-conserved canonical and non-canonical Wnt pathways are important for all aspects of mammalian development, including the development of the central nervous system. An outstanding question remains: how are the various Wnt pathways that regulate development integrated in vivo? Dvls are outstanding candidates to address this question, since these conserved proteins are required in all eukaryotes for both canonical and non-canonical Wnt pathways. We have uncovered partially unique but predominantly redundant functions among the three Dvl genes. Single mutants display some unique defects in social behavior and conotruncal heart development, while double Dvl mutants display severe neural tube defects (craniorachischisis) and severe cochlear defects. In further support of redundancy, Dvl1/2/3 triple mutants are unable to undergo gastrulation and do not form mesoderm. We plan to dissect the in vivo pathways that Dvls regulate normal development and are disrupted in the Dvl mutants to produce these phenotypes. We produced in vivo conditional alleles in mice for each of the Dvl genes as well as in vivo alleles that can distinguish either canonical Wnt of non-canonical Wnt/PCP pathway function. We used these alleles to provide definitive evidence that the craniorachischisis phenotype displayed by Dvl1;Dvl2 double mutants resulted from disruption of convergent extension movements via the Wnt/PCP pathway. We will use these tools to provide a comprehensive analysis of the role of the canonical Wnt and non-canonical Wnt/PCP pathways during neuronal development from the first development of neural folds during gastrulation and neurulation throughout neurogenesis and neuronal migration. Based on our published and preliminary data, we predict that Dvls and the pathways they regulate are critical at all stages of brain development. We will use the following specific aims: 1) Determine the role of canonical Wnt and non-canonical Wnt/PCP pathways during gastrulation in vivo; 2) Characterize the Dvl dependent pathways responsible for neural tube closure during neurulation; 3) Determine the role of Dvls and the canonical Wnt and non-canonical Wnt/PCP pathways during forebrain/midbrain-hindbrain development using double Dvl mutants; and 4) Determine the role of Dvls and the canonical Wnt and non-canonical Wnt/PCP pathways during forebrain/midbrain-hindbrain development using triple Dvl mutants.

描述（由申请人提供）：保守的经典和非经典 Wnt 通路对于哺乳动物发育的各个方面都很重要，包括中枢神经系统的发育。一个悬而未决的问题仍然存在：调节发育的各种 Wnt 通路如何在体内整合？ Dvls 是解决这个问题的杰出候选者，因为这些保守蛋白是所有真核生物中经典和非经典 Wnt 通路所必需的。我们发现了三个 Dvl 基因之间部分独特但主要是冗余的功能。单突变体在社会行为和圆锥干心脏发育方面表现出一些独特的缺陷，而双Dvl突变体则表现出严重的神经管缺陷（颅骨劈裂）和严重的耳蜗缺陷。为了进一步支持冗余，Dvl1/2/3 三重突变体无法经历原肠胚形成并且不形成中胚层。我们计划剖析 Dvl 调节正常发育以及在 Dvl 突变体中被破坏以产生这些表型的体内途径。我们在小鼠体内产生了每个 Dvl 基因的条件等位基因以及可以区分经典 Wnt 或非经典 Wnt/PCP 途径功能的体内等位基因。我们使用这些等位基因提供了明确的证据，证明 Dvl1;Dvl2 双突变体表现出的颅骨劈裂表型是由 Wnt/PCP 途径的会聚延伸运动破坏造成的。我们将使用这些工具对经典 Wnt 和非经典 Wnt/PCP 通路在神经元发育过程中的作用进行全面分析，从原肠胚形成和神经形成过程中神经褶皱的首次发育到整个神经发生和神经元迁移。根据我们已发表的初步数据，我们预测 Dvls 及其调节的通路在大脑发育的所有阶段都至关重要。我们将采用以下具体目标：1）确定经典Wnt和非经典Wnt/PCP通路在体内原肠胚形成过程中的作用； 2) 表征神经形成过程中负责神经管闭合的 Dvl 依赖性通路； 3) 使用双 Dvl 突变体确定 Dvls 以及经典 Wnt 和非经典 Wnt/PCP 通路在前脑/中脑-后脑发育过程中的作用； 4) 使用三重 Dvl 突变体确定 Dvls 以及典型 Wnt 和非典型 Wnt/PCP 通路在前脑/中脑-后脑发育过程中的作用。