Role of Lrp6 in the regulation of Wnt signaling during brain development

Lrp6 在大脑发育过程中 Wnt 信号传导的调节中的作用

• 批准号: 7586704
• 负责人: Jason D Gray
• 金额: $ 4.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586704
• 关键词: Adhesions; Affect; Amino Acid Substitution; Anencephaly; Antibodies; Autistic Disorder; Behavior; Binding; Brachyury protein; Brain; Calcium; Cell Adhesion; Cell Polarity; Cell Proliferation; Cell Shape; Cell Survival; Cells; Cellular Morphology; Cephalic; Chiroptera; Clinical; Complex; Cytoskeletal Modeling; Cytoskeleton; Data; Defect; Deformity; Dependence; Development; Developmental Process; Dorsal; Embryo; Event; Exencephalies; Extracellular Domain; Failure; Family; Fibroblasts; Folate; Gene Expression; Genes; Genetic; Genetic Crosses; Genetic Transcription; Gray unit of radiation dose; Guanosine Triphosphate Phosphohydrolases; Human; Image; Immunohistochemistry; In Situ Hybridization; Infant; Knowledge; Laboratories; Low Density Lipoprotein Receptor; Medial; Mental Retardation; Missense Mutation; Modeling; Monomeric GTP-Binding Proteins; Mood Disorders; Morphology; Mus; Mutant Strains Mice; Mutation; Names; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Nucleotides; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Process; Proteins; Public Health; Regulation; Reporter; Reporting; Role; Route; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Spinal Dysraphism; Supplementation; Tail; Testing; Work; Xenopus; anthrax toxin; density; insight; mouse model; mutant; novel; postnatal; prenatal; prevent; pup; receptor; response; rho; rho GTP-Binding Proteins

DESCRIPTION (provided by applicant): Neural tube defects (NTD) observed in the naturally occurring mutant mouse line Crooked tail (Cd) were recently shown by this laboratory to be associated with a missense mutation in the low density lipoprotein receptor 6 (Lrp6) gene, which encodes a coreceptor acting with Frizzled (Fz) in the wingless (Wnt) pathway. Wnt binding through Lrp6/Fz activates a ¿-catenin dependent signaling cascade (canonical) to affect TCF/LEF driven gene transcription and regulate numerous developmental processes, including neurulation. The Cd mutation results in hyperactive Wnt canonical signaling that cannot be inhibited by Dkk1, an antagonist of the Wnt pathway. While Lrp6 is most closely associated with canonical signaling, Wnt can also work through B-catenin independent routes (non-canonical), such as the planar cell polarity pathway (PCP). Noncanonical pathways affect changes in the cytoskeleton and thereby regulate cell polarity. Recently, PCP genes have been associated with NTDs in mouse and Xenopus. This proposal seeks to determine whether Lrp6 impacts neural tube closure through canonical or non-canonical Wnt signaling pathways. Either result would identify presently unrecognized Lrp6 functions, i.e. the ability of canonical Wnt signaling to regulate neurulation, the ability of Lrp6 to impact non-canonical pathways, or a possible Wnt signaling independent function for Lrp6. The morphological cause of failed neural tube closure in Cd and Lrp6-- mice will be examined using static and dynamic imaging, as well as immunohistochemistry and in situ hybridization. Non-canonical signaling will be examined by the Wnt dependent activation of small GTPases (Rho, Rac1, and Cdc42) in Cd and Lrp6-- mouse embryonic fibroblast (MEF) cells. Genetic crosses of Cd and Lrp6-- mice with mouse lines carrying deletions of other genes in the Wnt signaling pathway (Fz3) and canonical Wnt reporters (BatGal) will test the Wnt dependence of the neurulation defect and identify whether Lrp6 impacts NTDs primarily through the canonical or non-canonical pathway.Relevance to public health: Neural tube defects, such as spina bifida and anencephaly, affect 0.5 to 1 per thousand infants, and complex genetic interactions underlie their occurrence. This proposal will further characterize the function of the Lrp6 gene, which has been associated with neural tube defects, to advance our understanding of its potential action in clinical populations. Since Wnt signaling is also important in postnatal brain development, the knowledge gained from studying Lrp6 in neural tube development will also benefit patients suffering from mental retardation, autism and other behavior and mood disorders.

描述（由申请人提供）：在自然发生的突变小鼠系中观察到的神经管缺陷（NTD）该实验室最近表明，弯曲尾（Cd）与低密度脂蛋白受体6（Lrp6）基因中的错义突变有关，它编码与无翅 (Wnt) 通路中的卷曲 (Fz) 相互作用的辅助受体，通过 Lrp6/Fz 结合激活 ¿ -连环蛋白依赖性信号级联（典型）影响TCF/LEF驱动的基因转录并调节许多发育过程，包括神经形成。Cd突变导致Wnt典型信号传导过度活跃，而Dkk1是Wnt途径的拮抗剂。虽然 Wnt 与经典信号传导关系最为密切，但它还可以通过 B-连环蛋白独立途径（非经典）发挥作用，例如平面细胞极性途径 (PCP)。非经典途径影响细胞骨架的变化并调节细胞极性。最近，PCP 基因与小鼠和非洲爪蟾的 NTD 相关。该提案旨在确定 Lrp6 是否通过经典或非经典 Wnt 信号通路影响神经管闭合。识别目前未识别的 Lrp6 功能，即规范 Wnt 信号传导调节神经形成的能力、Lrp6 影响非规范途径的能力，或Lrp6 可能具有独立于 Wnt 信号传导的功能。将使用静态和动态成像以及免疫组织化学和非经典信号传导检查 Cd 和 Lrp6-- 小鼠神经管闭合失败的形态学原因。 Cd 和 Lrp6 中小 GTPase（Rho、Rac1 和 Cdc42）的 Wnt 依赖性激活 - 小鼠胚胎成纤维细胞 (MEF) 遗传杂交。 Cd 和 Lrp6——携带 Wnt 信号通路 (Fz3) 和规范 Wnt 产生者 (BatGal) 中其他基因缺失的小鼠品系的小鼠将测试神经细胞缺陷的 Wnt 依赖性，并确定 Lrp6 是否主要通过规范或非规范途径。与公共健康的相关性：神经管缺陷，如脊柱裂和无脑畸形，影响千分之 0.5 至 1 的婴儿，该提议将进一步描述与神经管缺陷相关的 Lrp6 基因的功能，以促进我们对其在临床人群中的潜在作用的理解，因为 Wnt 信号在出生后大脑中也很重要。研究Lrp6在神经管发育中所获得的知识也将使患有智力低下、自闭症和其他行为和情绪障碍的患者受益。