The Role of Actin Cables in Neural Tube Closure

肌动蛋白电缆在神经管闭合中的作用

• 批准号: 9192534
• 负责人: Philip C Spear
• 金额: $ 6万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192534
• 关键词: ABL1 gene; Actins; Actomyosin; Adhesives; Affect; Biological Assay; Birth; Boxing; Brain; CRISPR/Cas technology; Cell Culture Techniques; Cells; Cephalic; Clustered Regularly Interspaced Short Palindromic Repeats; Congenital Abnormality; Contracts; Cultured Cells; Cytoskeleton; DNA Sequence Alteration; Data; Development; Dominant-Negative Mutation; Ectoderm; Embryo; Embryo Deaths; Epithelial; Epithelial Cells; Epithelium; Event; Exencephalies; Extracellular Matrix; Failure; Figs - dietary; Focal Adhesions; Goals; Human; Human Cell Line; Lead; Life; Light; Microscopy; Molecular; Movement; Mus; Mutate; Mutation; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural tube; Outcomes Research; Paralysed; Pathway interactions; Point Mutation; Prevention; Process; Proteins; Quality of life; Regulation; Research; Research Project Grants; Risk Factors; Role; Side; Site; Spinal; Spinal Cord; Spinal Dysraphism; Study models; Surface Ectoderm; Testing; Time; Tissues; Transgenic Mice; Tube; Work; base; genetic risk factor; in vitro Assay; innovation; insight; meetings; migration; neural plate; null mutation; programs; relating to nervous system; repaired; research study; seal; time use

Project Summary The neural tube gives rise to the brain and spinal cord. The neural tube forms when a flat sheet of cells curls up and seals together. The surface ectoderm (SE) surrounds the folding neural tube and is required for the two sides of the tube to meet and close properly and ultimately for the neural tissue to be covered by an epithelial barrier. Failure to properly close and cover the neural tube results in neural tube defects including exencephaly and spina bifida. Neural tube defects are a common class of birth defects and can severely impact quality of life. In the cranial region, the SE reaches over the physical gap between the closing neural folds and then seals over the closing neural tube in a zippering fashion. Closing epithelial sheets often have actin cables that surround the site of closure and direct migration. Preliminary evidence from the Niswander lab suggests that the SE also has strong actin-rich cables at the leading edge. My research project aims to test the hypothesis that actin cables in the SE are regulated by the RhoA pathway to allow epithelial cells to reach over a gap to close the neural tube. My objectives are to determine how the actin cables close the SE and what proteins regulate actin cable formation and function in the SE. Characterization of actin cable function in the mouse embryo SE will be accomplished through time lapse microscopy and transgenic mice. Regulators of the RhoA pathway will be identified through cellular studies using a micropatterned in-vitro assay and CRISPR technology of a cultured human cell line. The long term goals of this research are to understand how neural tube closure is accomplished and to identify molecular mechanisms involved in neural tube closure. This research program will provide new insights into the function of the SE in neural tube closure and will identify the roles of some factors involved in the process. Outcomes of this research may facilitate the prevention and repair of neural tube defects.

项目摘要 神经管会产生大脑和脊髓。当细胞平坦的细胞卷曲时，神经管形成 向上密封。表面外胚层（SE）围绕着折叠神经管，两者是必需的 管的侧面以适当地相遇并最终使神经组织被上皮覆盖 障碍。未能正确关闭并覆盖神经管会导致神经管缺陷，包括外导管 和脊柱裂。神经管缺陷是一种常见的出生缺陷类别，可能会严重影响 生活。 在颅骨区域，SE到达闭合神经褶皱之间的物理间隙，然后密封 在闭合的神经管上，以一种扎根的方式。闭合上皮纸通常有肌动蛋白电缆 围绕关闭和直接迁移的地点。 Niswander Lab的初步证据表明 SE在前沿还具有强大的肌动蛋白电缆。我的研究项目旨在检验假设 SE中的肌动蛋白电缆受RhoA途径调节，以使上皮细胞超过一个间隙 关闭神经管。我的目标是确定肌动蛋白电缆如何关闭SE和什么蛋白 调节肌动蛋白电缆的形成和功能。鼠标中肌动蛋白电缆功能的表征 胚胎将通过延时显微镜和转基因小鼠来完成。 Rhoa的监管机构 将使用微图案中的体外测定法和CRISPR来识别途径 培养的人类细胞系的技术。这项研究的长期目标是了解神经 完成管闭合并确定与神经管闭合有关的分子机制。这 研究计划将为SE在神经管关闭中的功能提供新的见解，并将确定 在此过程中涉及的某些因素的作用。这项研究的结果可能有助于预防和 修复神经管缺陷。