Control of cell behavior during cranial neural tube closure

颅神经管闭合过程中细胞行为的控制

• 批准号: 9334622
• 负责人: Eric R Brooks
• 金额: $ 5.92万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-08 至 2019-08-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334622
• 关键词: Actins; Actomyosin; Address; Affect; Alpha Cell; Anterior; Apical; Area; Automobile Driving; Behavior; Behavioral; Brain; Cell Proliferation; Cell division; Cells; Cephalic; Cilia; Computer Analysis; Congenital Abnormality; Coupled; Defect; Development; Embryonic Structures; Epithelial; Erinaceidae; Etiology; Event; Failure; Genetic Transcription; Goals; Human; Human Development; Investigation; Lead; Link; Maps; Mediating; Morphogenesis; Mutation; Neural Tube Closure; Neural Tube Defects; Neural tube; Organelles; Pathway interactions; Phenotype; Play; Pregnancy; Process; Research; Resolution; Role; SHH gene; Shapes; Signal Pathway; Signal Transduction; Spinal Cord; Surface; Tissues; Tube; Vertebrates; behavioral outcome; cell behavior; cilium biogenesis; constriction; driving behavior; experimental study; imaging approach; insight; intercalation; mouse model; mutant; neural plate; neuroepithelium; smoothened signaling pathway; spatiotemporal; tool; transcriptome sequencing; transcriptomics

Abstract In vertebrates neural tube closure transforms the initially flat neuroepithelium into a closed, hollow tube that will give rise to the brain and spinal cord. Defects in this process are among the most common human birth defects, occurring in ~1:2000 pregnancies, and approximately half of these closure defects occur in the presumptive cranial region. However, we know very little about the cellular mechanisms that drive cranial closure, or how they are perturbed in mutants that fail at this process. Therefore, I propose to use a combination of imaging approaches coupled to quantitative cell wise computational analysis to characterize the cell behaviors, including apical constriction and cell proliferation, that drive cranial neural tube closure in the mouse model. Subsequently, I will examine how the cell behavioral profile is altered upon loss of cilia-mediated signaling thorough the Hedgehog pathway, which has been shown to lead to cranial closure defects. Finally, I will use transcriptomic approaches to parse the signaling pathways leading from cilia to cell behavior. Together, these experiments represent a significant advance in our understanding of the control of cell behaviors in cranial neural tube closure, a key concern in human development.

摘要 在脊椎动物中，神经管闭合将最初扁平的神经上皮转变为 形成大脑和脊髓的封闭的中空管。这一过程中的缺陷 是人类最常见的出生缺陷之一，发生在约1：2000的怀孕期间， 这些闭合缺陷中大约有一半发生在推测的颅骨区域。 然而，我们对驱动颅骨闭合的细胞机制知之甚少。 他们是如何对在这个过程中失败的突变体感到不安的。因此，我建议使用 与定量单元计算相结合的成像方法 分析细胞行为，包括根尖收缩和细胞 在小鼠模型中，导致脑神经管关闭的增殖。随后，我 将研究在纤毛介导的丧失时细胞的行为特征是如何改变的 信号通过Hedgehog通路，已被证明通向颅骨 关闭缺陷。最后，我将使用转录学方法来解析信号 从纤毛到细胞行为的通路。总而言之，这些实验代表了一个 我们对脑神经细胞行为控制的认识有了重大进展 管子关闭，这是人类发展中的一个关键问题。