Signaling dynamics in the control of ectoderm patterning and morphogenesis

项目摘要 神经形成是人类发育的一个关键阶段，此时神经系统形成模式，神经管 是成型的。很大一部分严重的出生缺陷以及植入后自然流产发生在 现阶段尽管它的重要性，这一阶段的人类发展几乎完全无法作为试管婴儿 胚胎在此之前不能培养，并且从这些早期阶段回收组织样品是罕见的。甚至 如果这种方法是可行的，它们也会带来道德上的难题。一个强大的新兴替代方案是创造自我- 从人类多能干细胞（hPSC）开始组织这些事件的模型。我们创造了两个- 三维系统，模仿外胚层内外轴的早期模式，是研究的理想选择。 包括神经系统、皮肤、神经嵴和感觉器官在内的外胚层命运的自组织。 我们还建立在这个系统上，以创建一个受控的三维系统， 形态发生使人联想到神经管闭合。在这里，我们建议完善这些模型，以及创建 新的模型的前-后轴，并使用这些模型与活细胞报告一起探测 通过Wnt、BMP和FGF途径的形态发生素信号传导之间的相互作用，沿着前-后-后-前-后-前-后-沿着 后（AP）和内外（ML）轴，和神经管形态发生。我们将解决关键问题 关于形态发生信号的空间模式是如何组织的，以及它们如何被细胞解释， 命运的模式和塑造组织的物理运动。综合起来，这些实验将 提供对外胚层模式和形态发生的深入了解，并建立研究出生缺陷的系统 与这个发展阶段有关。

Project Summary Neurulation is a crucial stage in human development when the nervous system is patterned, and the neural tube is shaped. A large fraction of severe birth defects as well as post-implantation spontaneous abortions occur at this stage. Despite its importance, this stage of human development is almost completely inaccessible as IVF embryos cannot be cultured until this point, and recovery of tissue samples from these early stages is rare. Even if such methods were possible, they present ethical dilemmas. A powerful emerging alternative is to create self- organizing models of these events starting from human pluripotent stem cells (hPSCs). We have created a two- dimensional system that mimics the early patterning of the ectodermal medial-lateral axis and is ideal for studying self-organization of ectodermal fates which include the nervous system, skin, neural crest, and sensory organs. We have also built upon this system to create a controlled three-dimensional system that undergoes reproducible morphogenesis reminiscent of neural tube closure. Here we propose to refine these models, as well as to create new models of the anterior-posterior axis, and to use these models together with live cell reporters to probe the interplay between morphogen signaling through the Wnt, BMP, and FGF pathways, patterning along the anterior- posterior (AP) and medial-lateral (ML) axes, and neural tube morphogenesis. We will address key questions about how spatial patterns of morphogen signals are organized and how they are interpreted by cells to give rise to patterns of fates and the physical movements that shape tissues. Taken together, these experiments will provide insight into ectodermal patterning and morphogenesis and establish a system for studying birth defects associated with this stage of development.