Control of cell behavior during cranial neural tube closure

摘要 在脊椎动物中，神经管闭合将最初平坦的神经上皮转变为 封闭的中空管，将产生大脑和脊髓。此过程中的缺陷 是最常见的人类出生缺陷之一，发生率约为1：2000怀孕， 并且这些闭合缺陷中的大约一半发生在假定的颅骨区域中。 然而，我们对驱动颅骨闭合的细胞机制知之甚少， 它们在突变体中是如何受到干扰的。因此，我建议使用 结合定量细胞计算的成像方法 分析以表征细胞行为，包括顶端收缩和细胞 增殖，其驱动小鼠模型中的颅神经管闭合。后来我 将研究细胞行为特征如何在纤毛介导的 Hedgehog信号通路，已被证明可导致颅 闭合缺陷。最后，我将使用转录组学方法来解析信号传导， 从纤毛到细胞行为的通路。总之，这些实验代表了 我们对脑神经细胞行为控制的理解取得了重大进展， 输卵管闭合是人类发展的一个关键问题。

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.