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: 7779487
• 负责人: Jason D Gray
• 金额: $ 3.19万
• 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/7779487
• 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（由适用提供）：该实验室最近显示出在天然发生的突变小鼠线弯曲的尾巴（CD）中观察到的神经管缺陷（NTD）与低密度脂蛋白受体6（LRP6）基因的错义突变相关，该基因与弗里兹（FEZ）无效（FZ）的作用（fz）中（fz）中的wing（fz）中（fz）中（fz）中（fz）。 Wnt通过LRP6/FZ的结合激活A€-Catenin依赖性信号级联（典型），以影响TCF/LEF驱动基因转录并调节包括神经化在内的许多发育过程。 CD突变导致Wnt途径的拮抗剂DKK1无法抑制过度活跃的Wnt典型信号传导。尽管LRP6与规范信号最密切相关，但WNT也可以通过B-catenin独立路线（非经典）（例如平面细胞极性途径（PCP））工作。非规范途径会影响细胞骨架的变化，从而调节细胞极性。最近，PCP基因与小鼠和爪蟾中的NTD相关。该建议旨在确定LRP6是否通过规范或非典型的Wnt信号通路影响神经元管的闭合。结果将确定目前未识别的LRP6函数，即规范Wnt信号调节神经化的能力，LRP6影响非典型途径的能力或LRP6可能的Wnt信号独立函数。 CD和LRP6中神经管闭合失败的形态原因将使用静态和动态成像，免疫组织化学和原位杂交检查。通过cd和lrp6--小鼠胚胎成纤维细胞（MEF）细胞中的小GTPases（Rho，Rac1和cdc42）的Wnt依赖性激活将检查非传统信号传导。 CD和LRP6-的遗传杂交与小鼠的遗传杂交具有携带Wnt信号通路中其他基因（FZ3）中其他基因的缺失的遗传交叉（BATGAL）测试神经元缺陷的Wnt依赖性，并确定LRP6是否会通过规范或非can nibube tandies tandies tandies tandies tandise defience.rif takire.rife nirectian.rife nirectian.rife nirection.rif.rif.rif.和跨脑，影响每千个婴儿0.5至1，而复杂的遗传相互作用是其发生的基础。该建议将进一步表征与神经元管缺陷相关的LRP6基因的功能，以促进我们对其在临床种群中的潜在作用的理解。由于Wnt信号在产后大脑的发育中也很重要，因此从研究LRP6中获得的知识也将使患有智力低下的患者，自闭症以及其他行为和其他情绪障碍受益。