Signaling dynamics in the control of ectoderm patterning and morphogenesis

项目摘要 神经形成是人类发育的关键阶段，神经系统是模式化的，神经管 是有形状的。很大一部分严重的出生缺陷和植入后的自然流产发生在 这个阶段。尽管它很重要，但人类发育的这一阶段几乎完全无法通过试管受精来实现 直到这一点，胚胎才能被培养，从这些早期阶段恢复组织样本的情况很少见。连 如果这样的方法是可能的，它们就会带来伦理困境。一种强大的新兴替代方案是创造自我 这些活动的组织模型始于人类多能干细胞(HPSCs)。我们创造了两个- 模拟外胚层内侧轴早期图案的维度系统，是研究的理想对象 外胚层命运的自组织，包括神经系统、皮肤、神经脊和感觉器官。 我们还在这个系统的基础上创造了一个可复制的受控三维系统 形态发生使人联想到神经管闭合。在这里，我们建议改进这些模型，并创建 前后轴的新模型，并使用这些模型与活细胞记者一起探索 通过Wnt、BMP和成纤维细胞生长因子通路的形态发生信号之间的相互作用，沿着前部- 后(AP)和内侧(ML)轴与神经管的形态发生。我们将解决关键问题 关于形态信号的空间模式是如何组织的，以及它们是如何被细胞解释以产生 命运的模式和塑造组织的身体运动。总而言之，这些实验将 洞察外胚层图案和形态发生，并建立研究出生缺陷的系统 与这一发展阶段相关的。

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.