Molecular Interactions During Neural Crest Formation

描述(由申请人提供)：这个项目的长期目标是促进我们对控制神经脊发育的细胞和分子机制的理解。神经脊细胞是脊椎动物特有的，出现在发育早期，广泛迁移并分化为几种衍生细胞，包括：头面部成分(肌肉和软骨等)、周围神经系统和皮肤的黑素细胞。神经脊发育和动态平衡的缺陷会导致被称为“神经病变”的人类疾病，包括唇腭裂、瓦登堡综合征和黑色素瘤等。提高我们对神经脊细胞生物学的理解是帮助诊断和治疗方法的基础。这个项目研究了神经脊形成的早期阶段，并着重于信号通路的贡献。这项工作以两个模型为中心--鸟类胚胎和基于人类胚胎干细胞的人类神经脊发育的新模型。在小鸡中，我们使用囊胚，而在人类干细胞模型中，我们解决了最早的分化时间点。在这两个模型中，Wnt和FGF信号通路的作用将被仔细研究，特别是转录效应器。目的1旨在阐明不同的成纤维细胞生长因子信号分支在囊胚期和原肠胚期的特异性贡献，并建立Pea3亚家族的差异反应和转录效应因子。目的2剖析主导的正则和替代的非正则WNT途径所作的贡献。这里将重点介绍转录因子Tcf和Lef。目的3将验证和有效的人类NC发育模型，并利用基于人类胚胎干细胞的高效和健壮的模型来建立这两个信号通路(成纤维细胞生长因子和Wnt)对人类神经脊发育的贡献。这项工作将阐明高等脊椎动物(鸟类和哺乳动物)神经峰形成的基本原理，并将为人类神经峰的研究注入活力。

DESCRIPTION (provided by applicant): The long term goal of this project is to advance our understanding of the cellular and molecular mechanisms that control neural crest development. Neural crest cells are vertebrate-specific, appear early in development, migrate extensively and differentiate into several derivatives, including: craniofacial components (muscle and cartilage amongst others), peripheral nervous system and melanocytes of the skin. Defects in neural crest development and homeostasis result in human pathologies known as "neurocristopathies" that include cleft lip/palate, Waardenburg syndrome, and melanoma, amongst others. Advancing our understanding of the biology of neural crest cells is fundamental to aid in diagnostic and therapeutic approaches. This project investigates early stages of neural crest formation, and focuses on the contributions made by signaling pathways. This work centers in two models - the avian embryo and a novel model of human neural crest development based on human embryonic stem cells. In the chick we utilize blastula embryos, while in the human stem cell model we address the earliest time points of differentiation. In both models, the role of Wnt and FGF signaling pathways will be scrutinized with particular focus on transcriptional effectors. Aim 1 is directed to elucidate the specific contributions made by distinct FGF-signaling branches during blastula and gastrula stages, and to establish differential responses and transcriptional effectors of the Pea3 sub-family. Aim 2 dissects the contributions made by the dominant canonical and alternative non- canonical Wnt pathways. Here emphasis will be directed to the transcriptional factors Tcf and Lef. Aim 3 will validate and eficcient model of human NC development, and establish the contributions made by these two signaling pathways (FGF, Wnt) to human neural crest development using an efficient and robust model based in human embryonic stem cells. This work will illuminate fundamental principles of neural crest formation in higher vertebrates (birds and mammals), and will invigorate human neural crest studies.